3,4-diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to COX-2 inhibitors

ABSTRACT

The invention encompasses the novel compound of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases. ##STR1## The invention also encompasses certain pharmaceutical compositions for treatment of cyclooxygenase-2 mediated diseases comprising compounds of Formula I.

BACKGROUND OF THE INVENTION

This invention relates to methods of treating cyclooxygenase mediateddiseases and certain pharmaceutical compositions therefor.

Nonosteroidal, antiinflammatory drugs exert most of theirantiinflammatory, analgesic and antipyretic activity and inhibithormone-induced uterine contractions and certain types of cancer growththrough inhibition of prostaglandin G/H synthase, also known ascyclooxygenase. Initially, only one form of cyclooxygenase was known,this corresponding to cyclooxygenase-1 (COX-1) or the constitutiveenzyme, as originally identified in bovine seminal vesicles. Morerecently the gene for a second inducible form of cyclooxygenase,cyclooxygenase-2 (COX-2) has been cloned, sequenced and characterizedinitially from chicken, murine and human sources. This enzyme isdistinct from the COX-1 which has been cloned, sequenced andcharacterized from various sources including the sheep, the mouse andman. The second form of cyclooxygenase, COX-2, is rapidly and readilyinducible by a number of agents including mitogens, endotoxin, hormones,cytokines and growth factors. As prostaglandins have both physiologicaland pathological roles, we have concluded that the constitutive enzyme,COX-1, is responsible, in large part, for endogenous basal release ofprostaglandins and hence is important in their physiological functionssuch as the maintenance of gastrointestinal integrity and renal bloodflow. In contrast, we have concluded that the inducible form, COX-2, ismainly responsible for the pathological effects of prostaglandins whererapid induction of the enzyme would occur in response to such agents asinflammatory agents, hormones, growth factors, and cytokines. Thus, aselective inhibitor of COX-2 will have similar antiinflammatory,antipyretic and analgesic properties to a conventional non-steroidalantiinflammatory drug, and in addition would inhibit hormone-induceduterine contractions and have potential anti-cancer effects, but willhave a diminished ability to induce some of the mechanism-based sideeffects. In particular, such a compound should have a reduced potentialfor gastrointestinal toxicity, a reduced potential for renal sideeffects, a reduced effect on bleeding times and possibly a lessenedability to induce asthma attacks in aspirin-sensitive asthmaticsubjects.

Furthermore, such a compound will also inhibit prostanoid-induced smoothmuscle contraction by preventing the synthesis of contractileprostanoids and hence may be of use in the treatment of dysmenorrhea,premature labour, asthma and eosinophil related disorders. It will alsobe of use in the treatment of Alzheimer's disease, for decreasing boneloss particularly in postmenopausal women (i.e. treatment ofosteoporosis) and for the treatment of glaucoma.

A brief description of the potential utility of cyclooxygenase-2inhibitors is given in an article by John Vane, Nature, Vol. 367, pp.215-216, 1994, and in an article in Drugs News and Perspectives, Vol. 7,pp. 501-512, 1994.

SUMMARY OF THE INVENTION

The invention encompasses the novel compound of Formula I as well as amethod of treating cyclooxygenase-2 mediated diseases comprisingadministration to a patient in need of such treatment of a non-toxictherapeutically effective amount of a compound of Formula I. Thesecompounds are prodrugs of compounds which inhibit COX-2 selectively overCOX-1. The prodrugs are converted in vivo to the selective inhibitors.##STR2##

The invention also encompasses certain pharmaceutical compositions fortreatment of cyclooxygenase-2 mediated diseases comprising compounds ofFormula I.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses the novel compound of Formula I as well as amethod of treating cyclooxygenase-2 mediated diseases comprisingadministration to a patient in need of such treatment of a non-toxictherapeutically effective amount of a compound of Formula I ##STR3## ora pharmaceutically acceptable salt thereof wherein: Y is selected fromthe group consisting of

(a) C(R⁶)(R⁷),

(b) O,

(c) S, and

(d) C═O;

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃,

(b) S(O)₂ NHR⁸,

(c) S(O)₂ NHC(O)CF₃,

(d) S(O)(NH)NH₂,

(e) S(O)(NH)NHC(O)CF₃,

(f) P(O)(CH₃)NH₂,

(g) P(O)(CH₃)₂, and

(h) C(S)NH₂ ;

R² is selected from the group consisting of

(a) NR¹⁰ R¹¹,

(b) SR¹¹,

(c) OR¹¹,

(d) R¹¹,

(e) C1-10alkenyl,

(f) C1-10alkynyl,

(g) unsubstituted, mono-, di-, tri- or tetra-substituted C₃ -C₁₀cycloalkenyl wherein the substituents are independently selected fromthe group consisting of

(1) halo,

(2) C₁₋₆ alkoxy,

(3) C₁₋₆ alkylthio,

(4) CN,

(5) CF₃,

(6) C₁₋₁₀ alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C₁₋₁₀ alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C₁₋₄ alkyl,

(12) --C₁₋₁₀ alkyl-CO₂ --R¹² ;

(13) benzyloxy,

(14) --O--(C₁₋₁₀ alkyl)-CO₂ R¹², and

(15) --O--(C₁₋₁₀ alkyl)-NR¹² R¹³ ;

(h) a mono-, di-, tri- or tetra-substituted heterocycloalkyl group of 5,6 or 7 members or a benzoheterocycle wherein said heterocycloalkyl orbenzoheterocycle contains 1 or 2 heteroatoms selected from O, S, or Nand optionally contains a carbonyl group or a sulfonyl group, andwherein said substituents are independently selected from the groupconsisting of

(1) halo,

(2) C₁₋₁₀ alkyl,

(3) C₁₋₁₀ alkoxy,

(4) C₁₋₁₀ alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl;

(i) styryl or mono or di-substituted styryl wherein the substituent areindependently selected from the group consisting of

(1) halo,

(2) C₁₋₆ alkoxy,

(3) C₁₋₆ alkylthio,

(4) CN,

(5) CF₃,

(6) C₁₋₁₀ alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C₁₋₁₀ alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C₁₋₄ alkyl,

(12) --C₁₋₁₀ alkyl-CO₂ --R¹² ;

(13) benzyloxy,

(14) --O--(C₁₋₁₀ alkyl)-CO₂ R¹², and

(15) --O--(C₁₋₁₀ alkyl)-NR¹² R¹³ ;

(j) phenylacetylene or mono- or di-substituted phenylacetylene whereinthe substituents are independently selected from the group consisting of

(1) halo,

(2) C₁₋₆ alkoxy,

(3) C₁₋₆ alkylthio,

(4) CN,

(5) CF₃,

(6) C₁₋₁₀ alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C₁₋₁₀ alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C₁₋₄ alkyl,

(12) --C₁₋₁₀ alkyl-CO₂ --R¹²,

(13) benzyloxy,

(14) --O--(C₁₋₁₀ alkyl)-CO₂ R¹²,

(15) --O--(C₁₋₁₀ alkyl)-NR¹² R¹³,

(k) C₁₋₁₀ fluoroalkenyl, and

(l) mono- or di-substituted bicyclic heteroaryl of 8, 9 or 10 members,containing 2, 3, 4 or 5 heteroatoms, wherein at least one heteroatomresides on each ring of said bicyclic heteroaryl, said heteroatomsindependently selected from O, S and N and said substituents areindependently selected from the group consisting of

(1) hydrogen,

(2) halo,

(3) C₁₋₁₀ alkyl,

(4) C₁₋₁₀ alkoxy,

(5) C₁₋₆ alkylthio,

(6) CN,

(7) C₁₋₆ fluoroalkyl, including CF₃,

(8) N₃,

(9) --C(R⁵)(R⁶)--OH,

(10) --C(R⁵)(R⁶)--O--C₁₋₁₀ alkyl;

R³ is hydrogen, C₁₋₁₀ alkyl, CH₂ OR⁸, CN, CH₂ CN, or C₁₋₆ fluoroalkyl,F, CONR⁸ ₂, unsubstituted or mono- or di-substituted phenyl,unsubstituted or mono or di-substituted benzyl, unsubstituted or mono-or di-substituted heteroaryl, unsubstituted or mono or di-substitutedheteroarylmethyl, wherein the substituents are independently selectedfrom the group consisting of

(1) halo,

(2) C₁₋₁₀ alkyl,

(3) C₁₋₁₀ alkoxy,

(4) C₁₋₁₀ alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl;

R³ is hydrogen, C₁₋₁₀ alkyl, CH₂ OR⁸, CN, CH₂ CN, or C₁₋₆ fluoroalkyl,F, CONR⁸ ₂, unsubstituted or mono- or di-substituted phenyl,unsubstituted or mono or di-substituted benzyl, unsubstituted or mono-or di-substituted heteroaryl, unsubstituted or mono or di-substitutedheteroarylmethyl, wherein the substituents are independently selectedfrom the group consisting of

(1) halo,

(2) C₁₋₁₀ alkyl,

(3) C₁₋₁₀ alkoxy,

(4) C₁₋₁₀ alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl;

R⁴ is

(a) hydrogen,

(b) C₁₋₁₀ alkyl,

(c) C₁₋₁₀ alkoxy,

(d) C₁₋₁₀ alkylthio,

(e) --OH,

(f) --OCOR⁸,

(g) --SH,

(h) --SCOR⁸,

(i) --OCO₂ R⁹,

(j) --SCO₂ R⁹,

(k) OCONR⁸ ₂,

(l) SCONR⁸ ₂ ;

(m) C₃₋₁₀ cycloalkoxy, and

(n) C₃₋₁₀ cycloalkylthio,

or R³ and R⁴ together with the carbon to which they are attached form amonocyclic ting of 3, 4, 5, 6, or 7 members which ring optionallycontains one or two heteroatoms selected from O, S or N;

R⁵ is selected from the group consisting of

(a) OR¹⁷,

(b) SR¹⁸,

(c) NR¹⁷ R¹⁸,

(d) NHS(O)₂ R¹⁸,

(e) S(O)R¹⁸,

(f) S(O)₂ R¹⁸,

(g) S(O)₂ NR¹⁷ ₂,

(h) OP(O)(OR¹⁶)₂ ;

R⁶ and R⁷ are independently

(a) hydrogen,

(b) unsubstituted or mono- or di-substituted phenyl or unsubstituted ormono- or di-substituted benzyl or unsubstituted or mono- ordi-substituted heteroaryl or mono- or di-substituted heteroarylmethyl,wherein said substituents are independently selected from the groupconsisting of:

(1) halo,

(2) C₁₋₁₀ alkyl,

(3) C₁₋₁₀ alkoxy,

(4) C₁₋₁₀ alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹⁴)(R¹⁵)--OH, and

(9) --C(R¹⁴)(R¹⁵)--O--C₁₋₁₀ alkyl, and

(c) C₁₋₁₀ alkyl, CH₂ OR⁸, CN, CH₂ CN, C₁₋₁₀ fluoroalkyl, CONR⁸ ₂, F orOR⁸,

or R⁶ and R⁷ together with the carbon to which they are attached form asaturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;

each R⁸ is independently selected from the group consisting of

(a) hydrogen and

(b) R⁹ ;

each R⁹ is independently selected from the group consisting of

(a) C₁₋₁₀ alkyl,

(b) --C₁₋₁₀ alkyl-CO₂ H

(c) C₁₋₁₀ alkyl-NH₂

(d) phenyl or mono-, di- or tri-substituted phenyl wherein thesubstituents are independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alklyCO₂ H, C₁₋₁₀ alkylNH₂, CN, CO₂ H andCF₃,

(e) benzyl or mono-, di- or tri-substituted benzyl wherein thesubstituents are independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylCO₂ H, C₁₋₁₀ alkylNH₂, CN, CO₂ H andCF₃,

(f) C₃₋₁₀ cycloalkyl,

(g) C₁₋₁₀ alkanoyl, and

(h) benzoyl or mono-, di-, or trisubstituted benzoyl wherein thesubstituents are independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylCO₂ H, --C₁₋₁₀ alkylNH₂, CN, CO₂ Hand CF₃,

each R¹⁰ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹¹ ;

R¹¹ is selected from the group consisting of

(a) C₁₋₁₀ alkyl,

(b) C₃₋₁₀ cycloalkyl,

(c) unsubstituted, mono-, di- or tri-substituted phenyl or naphthylwherein the substituents are independently selected from the groupconsisting of

(1) halo,

(2) C₁₋₁₀ alkoxy,

(3) C₁₋₁₀ alkylthio,

(4) CN,

(5) CF₃,

(6) C₁₋₁₀ alkyl,

(7) N₃,

(8) --CO₂ H,

(9) --CO₂ --C₁₋₁₀ alkyl,

(10) --C(R¹²)(R¹³)--OH,

(11) --C(R¹²)(R¹³)--O--C₁₋₄ alkyl,

(12) --C₁₋₆ alkyl-CO₂ --R¹²,

(13) benzyloxy,

(14) --O--(C₁₋₁₀ alkyl)-CO₂ R¹², and

(15) --O--(C₁₋₁₀ alkyl)-NR¹² R¹³,

(d) unsubstituted, mono-, di- or tri-substituted heteroaryl wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone hetero atom which is S, O, or N, and optionally 1, 2, or 3additional N atoms; or said heteroaryl is a monocyclic ring of 6 atoms,said ring having one hetero atom which is N, and optionally 1, 2, or 3additional N atoms, and wherein said substituents are independentlyselected from the group consisting of

(1) halo,

(2) C₁₋₁₀ alkyl,

(3) C₁₋₁₀ alkoxy,

(4) C₁₋₁₀ alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl;

(e) unsubstituted, mono- or di-substituted benzoheterocycle in which thebenzoheterocycle is a 5, 6, or 7-membered ring which contains 1 or 2heteroatoms independently selected from O, S, or N and optionally acarbonyl group or a sulfonyl group, wherein said substituents areselected from the group consisting of

(1) halo,

(2) C₁₋₁₀ alkyl,

(3) C₁₋₁₀ alkoxy,

(4) C₁₋₁₀ alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl;

(f) unsubstituted, mono- or di-substituted benzocarbocycle in which thecarbocycle is a 5, 6, or 7-membered ring which optionally contains acarbonyl group, wherein said substituents are independently selectedfrom the group consisting of

(1) halo,

(2) C₁₋₁₀ alkyl,

(3) C₁₋₁₀ alkoxy,

(4) C₁₋₁₀ alkylthio,

(5) CN,

(6) CF₃,

(7) N₃,

(8) --C(R¹²)(R¹³)--OH, and

(9) --C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl;

each R¹² or R¹³ is independently selected from the group consisting of

(a) hydrogen, and

(b) C₁₋₁₀ alkyl,

or R¹² and R¹³ together with the atom to which they are attached form asaturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;

R¹⁴ and R¹⁵ are independently selected from the group consisting of:

(a) hydrogen, and

(b) C₁₋₁₀ alkyl, or

R¹⁴ and R¹⁵ together with the carbon to which they are attached form acarbonyl, --C(═S)--, or a saturated monocyclic carbon ring of 3, 4, 5,6, or 7 atoms;

each R¹⁶ is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl and unsubstituted or mono- or disubstituted benzyl,wherein the substituents are selected from halo, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylthio or C₁₋₆ fluoroalkyl;

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C₁₋₁₀ alkyl,

(b) --C₁₋₁₀ alkyl-CO₂ H

(c) C₁₋₁₀ alkyl-NH₂

(d) phenyl or mono-, di- or tri-substituted phenyl wherein thesubstituents are independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alklyCO₂ H, C₁₋₁₀ alkylNH₂, CN, CO₂ H andCF₃,

(e) benzyl or mono-, di- or tri-substituted benzyl wherein thesubstituents are independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylCO₂ H, C₁₋₁₀ alkylNH₂, CN, CO₂ H andCF₃,

(f) C₃₋₁₀ cycloalkyl,

(g) H-(oxyethyl)n wherein n is 1 to 6.

(h) C₁₋₁₀ alkanoyl, and

(i) benzoyl or mono-, di-, or trisubstituted benzoyl wherein thesubstituents are independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylCO₂ H, --C₁₋₁₀ alkylNH₂, CN, CO₂ Hand CF₃, and

(j) --CONH-Ph-CO₂ R¹⁹ ; and

R¹⁹ is selected from the group consisting of hydrogen or C₁₋₆ alkyl.

Within this embodiment there is a genus of compounds wherein

R⁵ is selected from the group consisting of

(a) OR¹⁷,

(b) SR¹⁸, and

(c) NHS(O)₂ R¹⁸.

Within this genus there is a sub-genus of compounds wherein

Y is selected from the group consisting of

(a) C(R⁶)(R⁷), and

(b) O;

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃, and

(b) S(O)₂ NHR⁸ ;

R² is selected from the group consisting of

(a) OR¹¹,

(b) R¹¹,

(c) a mono-, di-, tri- or tetra-substituted heterocycloalkyl group of 5,6 or 7 members or a benzoheterocycle wherein said heterocycloalkyl orbenzoheterocycle contains 1 or 2 heteroatoms selected from O, S, or Nand optionally contains a carbonyl group or a sulfonyl group, andwherein said substituents are independently selected from the groupconsisting of

(1) halo,

(2) C₁₋₄ alkyl,

(3) C₁₋₄ alkoxy,

(4) C₁₋₄ alkylthio,

(5) CF₃, and

(6) --C(R¹²)(R¹³)--OH;

(d) phenylacetylene or mono- or di-substituted phenylacetylene whereinthe substituents are independently selected from the group consisting of

(1) halo,

(2) C₁₋₄ alkyl,

(3) C₁₋₄ alkoxy,

(4) C₁₋₄ alkylthio,

(5) CF₃, and

(6) --C(R¹²)(R¹³)--OH;

R³ is hydrogen, C₁₋₄ alkyl, CH₂ OH, or C₁₋₆ fluoroalkyl, F, CONH₂ ;

R⁴ is

(a) hydrogen,

(b) C₁₋₄ alkyl,

(c) C₁₋₄ alkoxy,

(d) C₁₋₄ alkylthio,

(e) --OH,

or R³ and R⁴ together with the carbon to which they are attached form amonocyclic ring of 3, 4, 5, 6, or 7 members which ring optionallycontains one or two heteroatoms selected from O, S or N;

R⁵ is selected from the group consisting of

(a) OR¹⁷, and

(b) SR¹⁸ ;

R⁶ and R⁷ are independently

(a) hydrogen,

(b) C₁₋₄ alkyl, CH₂ OH, CN, CH₂ CN, C₁₋₄ fluoroalkyl, CONH₂, F or OH,

or R⁶ and R⁷ together with the carbon to which they are attached form asaturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;

each R⁸ is independently selected from the group consisting of

(a) hydrogen and

(b) R⁹ ;

each R⁹ is independently selected from the group consisting of

(a) C₁₋₄ alkyl,

(b) --C₁₋₄ alkyl-CO₂ H

(c) phenyl or mono-, di- or tri-substituted phenyl wherein thesubstituents are independently selected from halo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, C₁₋₄ alklyCO₂ H, C₁₋₄ alkylNH₂, CN, CO₂ H andCF₃,

(f) C₃₋₆ cycloalkyl,

(g) C₁ -C₄ alkanoyl, and

(h) benzoyl or mono-, di-, or trisubstituted benzoyl wherein thesubstituents are independently selected from halo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylCO₂ H, --C₁₋₄ alkylNH₂, CN, CO₂ H andCF₃,

R¹¹ is selected from the group consisting of

(a) unsubstituted, mono- or di-substituted phenyl wherein thesubstituents are independently selected from the group consisting of

(1) halo,

(2) C₁₋₄ alkoxy,

(3) C₁₋₄ alkylthio,

(5) CF₃,

(6) C₁₋₄ alkyl,

(7) --CO₂ H,

(8) --CO₂ --C₁₋₆ alkyl,

(9) --C(R¹²)(R¹³)--OH,

(d) unsubstituted, mono- or di-substituted heteroaryl wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone hetero atom which is S, O, or N, and optionally 1, 2, or 3additional N atoms; or said heteroaryl is a monocyclic ring of 6 atoms,said ring having one hetero atom which is N, and optionally 1, 2, or 3additional N atoms, and wherein said substituents are independentlyselected from the group consisting of

(1) halo,

(2) C₁₋₄ alkoxy,

(3) C₁₋₄ alkylthio,

(4) CF₃,

(5) C₁₋₄ alkyl,

(6) --CO₂ H,

(7) --CO₂ --C₁₋₆ alkyl,

(8) --C(R¹²)(R¹³)--OH,

(e) unsubstituted, mono- or di-substituted benzoheterocycle in which thebenzoheterocycle is a 5, 6, or 7-membered ring which contains 1 or 2heteroatoms independently selected from O, S, or N and optionally acarbonyl group or a sulfonyl group, wherein said substituents areselected from the group consisting of

(1) halo,

(2) C₁₋₄ alkoxy,

(3) C₁₋₄ alkylthio,

(4) CF₃,

(5) C₁₋₄ alkyl,

(6) --CO₂ H,

(7) --CO₂ --C₁₋₆ alkyl,

(8) --C(R¹²)(R¹³)--OH,

(f) unsubstituted, mono- or di-substituted benzocarbocycle in which thecarbocycle is a 5, 6, or 7-membered ring which optionally contains acarbonyl group, wherein said substituents are independently selectedfrom the group consisting of

(1) halo,

(2) C₁₋₄ alkoxy,

(3) C₁₋₄ alkylthio,

(4) CF₃,

(5) C₁₋₄ alkyl,

(6) --CO₂ H,

(7) --CO₂ --C₁₋₆ alkyl,

(8) --C(R¹²)(R¹³)--OH,

each R¹² or R¹³ is independently selected from the group consisting of

(a) hydrogen, and

(b) C₁₋₆ alkyl,

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C₁₋₄ alkyl,

(b) --C₁₋₄ alkyl-CO₂ H

(c) C₁₋₆ alkanoyl, and

(d) H-(oxyethyl)n wherein n is 1 to 4.

Within this sub-genus there is a class of compounds wherein

Y is selected from the group consisting of

(a) C(R⁶)(R⁷), and

(b) O;

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃, and

(b) S(O)₂ NH₂ ;

R² is selected from the group consisting of

(a) OR¹¹,

(b) R¹¹,

(c) a mono- or di-substituted heterocycloalkyl group of 5 or 6 memberswherein said heterocycloalkyl contains 1 or 2 heteroatoms which is N andoptionally contains a carbonyl group, and wherein said substituents areindependently selected from the group consisting of

(1) Cl or F,

(2) C₁₋₂ alkyl, and

(3) C₁₋₂ alkoxy,

(d) phenylacetylene or mono- or di-substituted phenylacetylene whereinthe substituents are independently selected from the group consisting of

(1) Cl or F,

(2) C₁₋₂ alkyl, and

(3) C₁₋₂ alkoxy,

R³ is hydrogen, C₁₋₃ alkyl;

R⁴ is hydrogen, C₁₋₃ alkyl;

or R³ and R⁴ together with the carbon to which they are attached form amonocyclic ring of 3, 4, 5 or 6 carbon atoms;

R⁵ is selected from the group consisting of

(a) OR¹⁷, and

(b) SR¹⁸ ;

R⁶ and R⁷ are independently

(a) hydrogen,

(b) C₁₋₃ alkyl, CH₂ OH, C₁₋₃ fluoroalkyl, CONH₂, F or OH,

or R⁶ and R⁷ together with the carbon to which they are attached form asaturated monocyclic carbon ring of 3, 4, 5 or 6;

each R⁸ is independently selected from the group consisting of

(a) hydrogen and

(b) R⁹ ;

each R⁹ is independently selected from the group consisting of

(a) C₁₋₄ alkyl,

(b) --C₁₋₄ alkyl-CO₂ H

(f) C₃₋₆ cycloalkyl, and

(g) C₁₋₃ alkanoyl,

R¹¹ is selected from the group consisting of

(a) unsubstituted, mono- or di-substituted phenyl wherein thesubstituents are independently selected from the group consisting of

(1) F or Cl,

(2) C₁₋₄ alkoxy,

(3) C₁₋₄ alkylthio,

(5) CF₃,

(6) C₁₋₄ alkyl, and

(7) --CO₂ H,

(d) unsubstituted, mono- or di-substituted heteroaryl wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone hetero atom which is S, O, or N, and optionally 1, 2, or 3additional N atoms; or said heteroaryl is a monocyclic ring of 6 atoms,said ring having one hetero atom which is N, and optionally 1, 2, or 3additional N atoms, and wherein said substituents are independentlyselected from the group consisting of

(1) F or Cl,

(2) C₁₋₄ alkoxy,

(3) C₁₋₄ alkylthio,

(5) CF₃,

(6) C₁₋₄ alkyl, and

(7) --CO₂ H,

(e) unsubstituted, mono- or di-substituted benzoheterocycle in which thebenzoheterocycle is a 5 or 6-membered ring which contains 1 or 2heteroatoms independently selected from O, S, or N and optionally acarbonyl group or a sulfonyl group, wherein said substituents areselected from the group consisting of

(1) F or Cl,

(2) C₁₋₄ alkoxy,

(3) C₁₋₄ alkylthio,

(5) CF₃,

(6) C₁₋₄ alkyl, and

(7) --CO₂ H,

(f) unsubstituted, mono- or di-substituted benzocarbocycle in which thecarbocycle is a 5 or 6-membered ring which optionally contains acarbonyl group, wherein said substituents are independently selectedfrom the group consisting of

(1) F or Cl,

(2) C₁₋₄ alkoxy,

(3) C₁₋₄ alkylthio,

(5) CF₃,

(6) C₁₋₄ alkyl, and

(7) --CO₂ H,

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C₁₋₄ alkyl,

(b) --C₁₋₄ alkyl-CO₂ H

(c) C₁₋₆ alkanoyl, and

(d) H-(oxyethyl)n wherein n is 1 to 4.

Within this class there is a sub-class of compounds wherein

Y is selected from the group consisting of

(a) CH₂, and

(b) O;

R¹ is selected from the group consisting of

(a) S(O)₂ CH₃, and

(b) S(O)₂ NH₂ ;

R² is selected from the group consisting of

(a) OR¹¹,

(b) R¹¹,

(c) a mono- or di-substituted heterocycloalkyl group of 5 or 6 memberswherein said heterocycloalkyl contains 1 or 2 heteroatoms which is N andoptionally contains a carbonyl group, and wherein said substituents areindependently selected from the group consisting of

(1) Cl or F,

(2) C₁₋₂ alkyl, and

(3) C₁₋₂ alkoxy;

R³ is hydrogen, methyl or ethyl;

R⁴ is hydrogen, methyl or ethyl;

R⁵ is OR¹⁷ ;

R¹¹ is selected from the group consisting of

(a) unsubstituted, mono- or di-substituted phenyl wherein thesubstituents are independently selected from the group consisting of

(1) F or Cl,

(2) C₁₋₄ alkoxy,

(3) C₁₋₄ alkylthio,

(5) CF₃,

(6) C₁₋₄ alkyl, and

(7) --CO₂ H,

(b) unsubstituted, mono- or di-substituted heteroaryl wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone hetero atom which is S, O, or N, and optionally 1, 2, or 3additional N atoms; or said heteroaryl is a monocyclic ring of 6 atoms,said ring having one hetero atom which is N, and optionally 1, 2, or 3additional N atoms, and wherein said substituents are independentlyselected from the group consisting of

(1) F or Cl,

(2) C₁₋₄ alkoxy,

(3) C₁₋₄ alkylthio,

(5) CF₃,

(6) C₁₋₄ alkyl, and

(7) --CO₂ H,

each R¹⁷ is independently selected from the group consisting of

(a) hydrogen and

(b) R¹⁸ ; and

each R¹⁸ is independently selected from the group consisting of

(a) C₁₋₄ alkyl,

(b) --C₁₋₄ alkyl-CO₂ H

(c) C₁₋₆ alkanoyl, and

(d) H-(oxyethyl)n wherein n is 2, 3 or 4.

Also within this class there is a sub-class of compounds wherein

R² is a mono- or di-substituted heteroaryl wherein heteroaryl isselected from the group consisting of

(1) furanyl,

(2) diazinyl,

(3) imidazolyl,

(4) isooxazolyl,

(5) isothiazolyl,

(6) oxadiazolyl,

(7) oxazolyl,

(8) pyrazolyl,

(9) pyridyl,

(10) pyrrolyl,

(11) tetrazinyl

(12) tetrazolyl.

(13) thiadiazolyl,

(14) thiazolyl,

(15) thienyl,

(16) triazinyl, or

(17) triazolyl, and the substituents are selected from the groupconsisting of

(1) hydrogen,

(2) halo,

(3) C₁₋₄ alkyl,

(4) C₁₋₄ alkoxy,

(5) C₁₋₄ alkylthio,

(6) CN, and

(7) CF₃.

Within this sub-class are the compounds wherein

R² is a mono- or di-substituted heteroaryl wherein heteroaryl isselected from the group consisting of

(1) furanyl,

(2) diazinyl,

(3) imidazolyl,

(4) oxadiazolyl,

(5) pyrazolyl,

(6) pyridyl,

(7) pyrrolyl,

(8) thiazolyl,

(9) thienyl, wherein the substituents are selected from the groupconsisting of

(1) hydrogen,

(2) halo,

(3) methyl,

(4) methoxy, and

(5) CF₃.

For purposes of this specification, in situations in which a term occurstwo or more times such as "R⁸ " in "CONR⁸ ₂ " or R¹⁶ " in "OP(O)(OR¹⁶)₂", the definition of the term in each occurrence is independent of thedefinition in each additional occurrence. Similarly, each occurrence ofdefinitions such as R¹² and R¹³ are to be considered independent of eachadditional occurrence.

For purposes of this specification heteroaryl as in R³, R⁶, R⁷ and R¹¹is intended to include, but is not limited to optionally mono- ordi-substituted

(1) furanyl,

(2) diazinyl,

(3) imidazolyl,

(4) isooxazolyl,

(5) isothiazolyl,

(6) oxadiazolyl,

(7) oxazolyl,

(8) pyrazolyl,

(9) pyridyl,

(10) pyrrolyl,

(11) tetrazinyl

(12) tetrazolyl.

(13) thiadiazolyl,

(14) thiazolyl,

(15) thienyl,

(16) triazinyl, and

(17) triazolyl.

Similarly, for purposes of this specification cyclic groups such as aheterocycloalkyl or benzocarbocycle or benzoheterocycle such as in R²and R¹¹ is intended to include, but is not limited to optionally mono-or di-substituted

(1) tetrahydrothiopyranyl,

(2) thiomorpholinyl,

(3) pyrrolidinyl,

(4) hexahydroazepinyl,

(5) indanyl,

(6) tetralinyl,

(7) indolyl,

(8) benzofuranyl,

(9) benzothienyl,

(10) benzimidazolyl,

(11) benzothiazolyl, ##STR4##

Similarly, for purposes of this specification bicyclic heteroaryl as inR² is intended to include, but is not limited to optionally mono- ordi-substituted ##STR5##

One preferred genus is directed to the compounds of formula I wherein Yis O.

Another preferred genus is directed to compounds of Formula I wherein R³and R⁴ are each hydrogen.

Another preferred genus is directed to compounds of Formula I wherein R³is methyl and R⁴ is methyl or ethyl.

Another preferred genus is directed to compounds of Formula I wherein R²is a phenyl or substituted phenyl.

Another preferred genus is directed to compounds of Formula I wherein R²is a OR¹¹.

Another preferred genus is directed to compounds of Formula I R⁵ ishydroxy.

The invention is illustrated by the compounds of the Examples disclosedherein as well as the compounds of Table I:

(a)5,5-Dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(b)3-(3,5-Difluorophenyl)-5,5-dimethyl-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(c)5,5-Dimethyl-3-(4-fluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(d)5,5-Dimethyl-3-(4-fluorophenyl)-2-methoxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(e)5,5-Dimethyl-2-ethoxy-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(f)5,5-Dimethyl-3-(3-fluorophenyl)-2-isopropoxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(g)5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-methylthio-2,5-dihydrofuran,

(h)5-Ethyl-3-(4-fluorophenyl)-2-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(i)5,5-Dimethyl-3-(3-fluorophenoxy)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(j)5,5-Dimethyl-3-(3,4-difluorophenoxy)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(k)3-(3,4-Difluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(l) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-ol,

(m) 3-(4-(Methylsulfonyl)phenyl)-2-phenyl-2-cyclopenten-1-ol,

(n)2-Acetoxy-5,5-dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,

(o)2-(3,5-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-ol,

(p)Sodium(5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2,5-dihydrofuran-2-yloxy)actetate,and

(q) Succinic acidmono-(3-(4-(methylsulfonyl)phenyl)-2-phenylcyclopent-2-enyl)ester.

The following abbreviations have the indicated meanings:

AA=arachidonic acid

Ac=acetyl

AIBN=2.2-azobisisobutyronitrile

Bn=benzyl

CHO=chinese hamster ovary

CMC=1-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-p-toluenesulfonate

COX=cyclooxygenase

DBU=diazabicyclo 5.4.0!undec-7-ene

DMAP=4-(dimethylamino)pyridine

DMF=N,N-dimethylformamide

DMSO=dimethyl sulfoxide

Et₃ N=triethylamine

HBSS=Hanks balanced salt solution

HEPES=N- 2-Hydroxyethyl!piperazine-N¹ - 2-ethanesulfonic acid!

HWB=human whole blood

KHMDS=potassium hexamethyldisilazane

LDA=lithium diisopropylamide

LPS=lipopolysaccharide

mCPBA=metachloro perbenzoic acid

MMPP=magnesium monoperoxyphthalate

Ms=methanesulfonyl=mesyl

MsO=methanesulfonate=mesylate

NBS=N-bromosuccinimide

NCS=N-chlorosuccinimide

NIS=N-iodosuccinimide

NSAID=non-steroidal anti-inflammatory drag

Oxone®=potassium peroxymonosulfate

PCC=pyridinium chlorochromate

PDC=pyridinium dichromate

r.t.=room temperature

rac.=racemic

Tf=trifluoromethanesulfonyl=triflyl

TFAA=trifluoroacetic anhydride

TfO=trifluoromethanesulfonate=triflate

THF=tetrahydrofuran

TLC=thin layer chromatography

TMPD=N,N,N',N'-tetramethyl-p-phenylenediamine

Ts=p-toluenesulfonyl=tosyl

TsO=p-toluenesulfonate=tosylate

Tz=1H (or 2H)-tetrazol-5-yl

SO₂ Me=methyl sulfone (also SO₂ CH₃)

SO₂ NH₂ =sulfonamide

    ______________________________________                                        Alkyl group abbreviations                                                                    Dose Abbreviations                                             ______________________________________                                        Me = methyl    bid = bis in die = twice daily                                 Et = ethyl     qid = quater in die = four times a day                         n-Pr = normal propyl                                                                         tid = ter in die = three times a day                           i-Pr = isopropyl                                                              n-Bu = normal butyl                                                           i-Bu = isobutyl                                                               s-Bu = secondary butyl                                                        t-Bu = tertiary butyl                                                         c-Pr = cyclopropyl                                                            c-Bu = cyclobutyl                                                             c-Pen = cyclopentyl                                                           c-Hex = cyclohexyl                                                            ______________________________________                                    

For purposes of this specification alkyl, alkenyl and alkynyl meanslinear branched and cyclic structures, and combinations thereof,containing the indicated number of carbon atoms. Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl,pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl,tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl,cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl,2-ethyl-1-bicyclo 4.4.0!decyl and the like.

For purposes of this specification fluoro alkyl means alkyl groups inwhich one or more hydrogen is replaced by fluorine. Examples are --CF₃,--CH₂ CH₂ F, --CH₂ CF₃, c-Pr-F₅, c-Hex-F₁₁ and the like.

Fluoroalkenyl includes alkenyl groups in which one or more hydrogen isreplaced by fluorine. Examples are --CH═CF₂, --CH═CHCF₃, --C(CF₃)═CMe₂,--CH═C(CH₃)CH₂ CF₃, --CH═CH(CH₂ F) and the like.

Cycloalkyl refers to a hydrocarbon, containing one or more rings havingthe indicated number of carbon atoms. Examples of cycloalkyl groups arecyclopropyl, cyclopentyl, cycloheptyl, aldamantyl, cyclododecyl,1-bicyclo 4.4.0!decyl and the like.

Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl,hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,5-decen-1-yl, 2-dodecen-1-yl and the like.

For purposes of this specification, cycloalkenyl means alkenyl groups ofthe indicated number of carbon atoms, which include a ring, and in whichthe alkenyl double bond may be located anywhere in the structure.Examples of cycloalkenyl groups are cyclopropen-1-yl, cyclohexen-3-yl,2-vinyladamant-1-yl, 5-methylenecyclododec-1-yl, and the like.

For purposes of this specification, the term alkynyl and means analkynyl groups of the indicated number of carbon atoms. Examples ofalkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl,2-heptynyl, 2-pentadecyn-1-yl, 1-eicosyn-1-yl, and the like.

For purposes of this specification, cycloalkynyl means groups of 5 to 20carbon atoms, which include a ring of 3 to 20 carbon atoms. The alkynyltriple bond may be located anywhere in the group, with the proviso thatif it is within a ring, such a ring must be 10 members or greater.Examples of "cycloalkynyl" are cyclododecyn-3-yl,3-cyclohexyl-1-propyn-1-yl, and the like.

For purposes of this specification alkoxy means alkoxy groups of theindicated number of carbon atoms of a straight, branched, or cyclicconfiguration. Examples of alkoxy groups include methoxy, ethoxy,propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.

For purposes of this specification alkylthio means alkylthio groups ofthe indicated number of carbon atoms of a straight, branched or cyclicconfiguration. Examples of alkylthio groups include methylthio,propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration,the propylthio group signifies --SCH₂ CH₂ CH₃.

For purposes of this specification Halo means F, Cl, Br, or I.

For purposes of this specification, the heterocycles formed when R¹² andR¹³ join through N include azetidine, pyrrolidine, piperidine, andhexahydroazepine.

Some of the compounds described herein contain one or more asymmetriccenters and may thus give rise to diastereomers and optical isomers. Thepresent invention is meant to comprehend such possible diastereomers aswell as their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The Compound of Formula I is useful for the relief of pain, fever andinflammation of a variety of conditions including rheumatic fever,symptoms associated with influenza or other viral infections, commoncold, low back and neck pain, dysmenorrhea, headache, toothache, sprainsand strains, myositis, neuralgia, synovitis, arthritis, includingrheumatoid arthritis, degenerative joint diseases (osteoarthritis), goutand ankylosing spondylitis, bursitis, bums, injuries, following surgicaland dental procedures. In addition, such a compound may inhibit cellularneoplastic transformations and metastic tumour growth and hence can beused in the treatment of cancer. Compound 1 may also be of use in thetreatment and/or prevention of cyclooxygenase-mediated proliferativedisorders such as may occur in diabetic retinopathy and tumourangiogenesis.

Compound I, by virtue of its in vivo conversion to a COX-2 inhibitor,will also inhibit prostanoid-induced smooth muscle contraction bypreventing the synthesis of contractile prostanoids and hence may be ofuse in the treatment of dysmenorrhea, premature labour, asthma andeosinophil related disorders. It will also be of use in the treatment ofAlzheimer's disease, for decreasing bone loss particularly inpostmenopausal women (i.e. treatment of osteoporosis), and for treatmentof glaucoma.

The compounds of Formula I are prodrugs of selective COX-2 inhibitors,and exert their action by conversion in vivo to these active andselective COX-2 inhibitors. The active compounds formed from thecompounds of the present invention are described in the followingdocuments which are hereby encorporated by reference:

WO 95/00501, published Jan. 5, 1995.

In certain respects, compounds of the present invention have advantagesover the compounds described in these documents by virtue of improvedpharmacokinetic and/or safety profiles. A general description of theadvantages and uses of prodrugs as pharmaceutically useful compounds isgiven in an article by Waller and George in Br. J. Clin. Pharmac. Vol.28, pp. 497-507, 1989.

By way of illustration, the following compounds of the present inventionare converted to the indicated COX-2 selective inhibitors.

    __________________________________________________________________________    Example                                                                            Prodrug                   Active Drug                                                                              Reference                           __________________________________________________________________________          ##STR6##                                                                                           ##STR7##       WO 95/00501                         10                                                                                  ##STR8##                                                                                           ##STR9##                                           13                                                                                  ##STR10##                                                                                          ##STR11##      WO 95/00501                         5                                                                                   ##STR12##                                                                                          ##STR13##      WO 95/00501                         39                                                                                  ##STR14##                                                                                          ##STR15##                                          40                                                                                  ##STR16##                                                                                          ##STR17##      WO 95/00501                         __________________________________________________________________________

By virtue of its in vivo conversion to a compound with high inhibitoryactivity against COX-2 and/or a specificity for COX-2 over COX-1,compound I will prove useful as an alternative to conventional NSAID'S,particularly where such non-steroidal antiinflammatory drugs may becontra-indicated such as in patients with peptic ulcers, gastritis,regional enteritis, ulcerative colitis, diverticulitis or with arecurrent history of gastrointestinal lesions; GI bleeding, coagulationdisorders including anaemia such as hypoprothrombinemia, haemophilia orother bleeding problems; kidney disease; those prior to surgery ortaking anticoagulants.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt, thereof, and may also contain a pharmaceuticallyacceptable carder and optionally other therapeutic ingredients. The term"pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium, and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like, and basic ion exchange resins.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts.

The compound of Formula I is useful for the relief of pain, fever andinflammation of a variety of conditions including rheumatic fever,symptoms associated with influenza or other viral infections, commoncold, low back and neck pain, dysmenorrhea, headache, toothache, sprainsand strains, myositis, neuralgia, synovitis, arthritis, includingrheumatoid arthritis, degenerative joint diseases (osteoarthritis), goutand ankylosing spondylitis, bursitis, bums, injuries, following surgicaland dental procedures. In addition, such a compound may inhibit cellularneoplastic transformations and metastic tumor growth and hence can beused in the treatment of cancer. Compound I may also be of use in thetreatment and/or prevention of cyclooxygenase-mediated proliferativedisorders such as may occur in diabetic retinopathy and tumourangiogenesis.

Compound I will also inhibit prostanoid-induced smooth musclecontraction by preventing the synthesis of contractile prostanoids andhence may be of use in the treatment of dysmenorrhea, premature labor,asthma and eosinophil related disorders. It will also be of use in thetreatment of Alzheimer's disease, and for the prevention of bone loss(treatment of osteoporosis) and for the treatment of glaucoma.

By virtue of its high cyclooxygenase-2 (COX-2) activity and/or itsspecificity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1), CompoundI will prove useful as an alternative to conventional non-steroidalantiinflammatory drugs (NSAID'S) particularly where such non-steroidalantiinflammatory drugs may be contra-indicated such as in patients withpeptic ulcers, gastritis, regional enteritis, ulcerative colitis,diverticulitis or with a recurrent history of gastrointestinal lesions;GI bleeding, coagulation disorders including anemia such ashypoprothrombinemia, haemophilia or other bleeding problems; kidneydisease; those prior to surgery or taking anticoagulants.

Similarly, Compound I, will be useful as a partial or completesubstitute for conventional NSAID'S in preparations wherein they arepresently co-administered with other agents or ingredients. Thus infurther aspects, the invention encompasses pharmaceutical compositionsfor treating cyclooxygenase-2 mediated diseases as defined abovecomprising a non-toxic therapeutically effective amount of the compoundof Formula I as defined above and one or more ingredients such asanother pain reliever including acetominophen or phenacetin; apotentiator including caffeine; an H₂ -antagonist, aluminum or magnesiumhydroxide, simethicone, a decongestant including phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxyephedrine; anantiitussive including codeine, hydrocodone, caramiphen, carbetapentane,or dextramethorphan; a prostaglandin including misoprostol, enprostil,rioprostil, ornoprostol or rosaprostol; a diuretic; a sedating ornon-sedating antihistamine. In addition the invention encompasses amethod of treating cyclooxygenase mediated diseases comprising:administration to a patient in need of such treatment a non-toxictherapeutically effective amount of the compound of Formula I,optionally co-administered with one or more of such ingredients aslisted immediately above.

For the treatment of any of these cyclooxygenase mediated diseasesCompound I may be administered orally, topically, parenterally, byinhalation spray or rectally in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carders, adjuvantsand vehicles. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. In addition to the treatment of warm-bloodedanimals such as mice, rats, horses, cattle sheep, dogs, cats, etc., thecompound of the invention is effective in the treatment of humans.

As indicated above, pharmaceutical compositions for treatingcyclooxygenase-2 mediated diseases as defined may optionally include oneor more ingredients as listed above.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be,for example, inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed with water ormiscible solvents such as propylene glycol, PEGs and ethanol, or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oil, or a mineral oil, for example, liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example, soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleagenous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butane diol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. Cosolvents such as ethanol, propylene glycol or polyethyleneglycols may also be used. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Compound I may also be administered in the form of a suppositories forrectal administration of the drug. These compositions can be prepared bymixing the drug with a suitable non-irritating excipient which is solidat ordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials arecocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.) Topical formulations may generally be comprised of apharmaceutical carrier, cosolvent, emulsifier, penetration enhancer,preservative system, and emollient.

Dosage levels of the order of from about 0.01 mg to about 140 mg/kg ofbody weight per day are useful in the treatment of the above-indicatedconditions, or alternatively about 0.5 mg to about 7 g per patient perday. For example, inflammation may be effectively treated by theadministration of from about 0.01 to 50 mg of the compound per kilogramof body weight per day, or alternatively about 0.5 mg to about 3.5 g perpatient per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 g of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 800 mg, or 1000 mg.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

The compounds of the present invention can be prepared according to thefollowing methods ##STR18## Compound Ia may be prepared by the treatmentof a THF solution of carbonyl compound II (WO 9500501, published Jun. 5,1995) with a reducing agent such as DIBAL at 0° C. See also the startingmaterials section which follows the Examples. ##STR19## Compound Ic maybe prepared by the treatment of lactol Ib with an appropriate alcohol,mercaptan or amine in the presence of an acid catalyst such as BF₃.OEt₂or H₂ SO₄. ##STR20## Compounds Id and Ie may be prepared by treatment ofsulfide Ic with one or two equivalents respectively of an oxidizingagent such as OXONE, mCPBA or MMPP. ##STR21## Compound If may beprepared by treatment of compound Ia with an acid anhydride in thepresence of DMAP. ##STR22##

An appropriately substituted aryl dialkylhydroxyketone III is reactedwith an appropriately substituted acetic acid IV in a solvent such asdichloromethane in the presence of an esterifying agent such as1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate(CMC) and N,N-dimethylaminopyridine to provide ester V. Treatment with1,8-diazabicyclo 5.4.0!undec-7-ene (DBU) then affords lactone VI.Subsequent reduction of VI as indicated in Method A provides Ig which isan example of the current invention. ##STR23## Compound Ih may beprepared by treatment of compound Ia with an appropriate aryl isocyanatein the presence of a base. Hydrolysis of Ih with a base in an aqueousmedium affords compound Ii.

Representative Compounds

Table I illustrates compounds of formula I, which are representative ofthe present invention.

                                      TABLE I                                     __________________________________________________________________________     ##STR24##                                                                    Example                                                                            R    R.sup.2                                                                             R.sup.3                                                                             R.sup.4                                                                         R.sup.5                                                                             Y  Method                                       __________________________________________________________________________     1   Me   3-F-Ph                                                                              Me    Me                                                                              OH    O  A                                             2   Me   3,5-F.sub.2 -Ph                                                                     Me    Me                                                                              OH    O  A                                             3   Me   4-F-Ph                                                                              Me    Me                                                                              OH    O  A                                             4   Me   4-F-Ph                                                                              Me    Me                                                                              OMe   O  B                                             5   Me   3-F-Ph                                                                              Me    Me                                                                              OEt   O  B                                             6   Me   3-F-Ph                                                                              Me    Me                                                                              OiPr  O  B                                             7   Me   3-F-Ph                                                                              Me    Me                                                                              SMe   O  B                                             8   Me   3-F-Ph                                                                              Et    Me                                                                              OH    O  A                                             9   Me   3-F-PhO                                                                             Me    Me                                                                              OH    O  E                                            10   Me   3,4-F.sub.2 -PhO                                                                    Me    Me                                                                              OH    O  E                                            11   Me   3,4-F.sub.2 -Ph                                                                     H     H OH    O  A                                            12   Me   4-F-Ph                                                                              H     H OH    CH.sub.2                                                                         A                                            13   Me   Ph    H     H OH    CH.sub.2                                                                         A                                            14   Me   3-F-Ph                                                                              Me    Me                                                                              OAc   O  D                                            15   Me   2,6-F.sub.2 -Ph                                                                     Me    Me                                                                              OH    O  A                                            16   Me   3-Cl-Ph                                                                             H     H OH    CH.sub.2                                                                         A                                            17   Me   3,5-F.sub.2 -Ph                                                                     H     H OH    CH.sub.2                                                                         A                                            18   Me   3,5-Cl.sub.2 -Ph                                                                    H     H OH    CH.sub.2                                                                         A                                            19   NH.sub.2                                                                           3,5-F.sub.2 -Ph                                                                     Me    Me                                                                              OH    O  A                                            __________________________________________________________________________    Example                          Method                                       __________________________________________________________________________    20                                                                                  ##STR25##                  B                                            21                                                                                  ##STR26##                  D                                            22                                                                                  ##STR27##                                                               23                                                                                  ##STR28##                  B                                            24                                                                                  ##STR29##                  C                                            25                                                                                  ##STR30##                  B                                            26                                                                                  ##STR31##                  A                                            27                                                                                  ##STR32##                  B                                            28                                                                                  ##STR33##                  B                                            29                                                                                  ##STR34##                  A                                            30                                                                                  ##STR35##                  A                                            31                                                                                  ##STR36##                  B                                            32                                                                                  ##STR37##                  A                                            33                                                                                  ##STR38##                  A                                            34                                                                                  ##STR39##                  A                                            35                                                                                  ##STR40##                  A                                            36                                                                                  ##STR41##                  A + B                                        37                                                                                  ##STR42##                  A + B                                        38                                                                                  ##STR43##                  A                                            39                                                                                  ##STR44##                  A                                            40                                                                                  ##STR45##                  A                                            41                                                                                  ##STR46##                  A                                            42                                                                                  ##STR47##                  A                                            43                                                                                  ##STR48##                  A                                            44                                                                                  ##STR49##                  A                                            45                                                                                  ##STR50##                  A                                            46                                                                                  ##STR51##                  A                                            47                                                                                  ##STR52##                  A + F                                        48                                                                                  ##STR53##                  A + F                                        __________________________________________________________________________

Assays for determining Biological Activity

The compound of Formula I can be tested using the following assays todetermine their cyclooxygenase-2 inhibiting activity.

INHIBITION OF CYCLOOXYGENASE ACTIVITY

Compounds are tested as inhibitors of cyclooxygenase activity in wholecell cyclooxygenase assays. Both of these assays measure prostaglandinE₂ synthesis in response to arachidonic acid, using a radioimmunoassay.In these assays, 100% activity is defined as the difference betweenprostaglandin E₂ synthesis in the absence and presence of arachidonate.

Whole Cell Assays

For cyclooxygenase assays, osteosarcoma cells are cultured in 1 mL ofmedia in 24-well multidishes (Nunclon) until confluent (1-2×10⁵cells/well). U-937 cells are grown in spinner flasks and resuspended toa final density of 1.5×10⁶ cells/mL in 24-well multidishes (Nunclon).Following washing and resuspension of osteosarcoma and U-937 cells in 1mL of HBSS, 1 μL of a DMSO solution of test compound or DMSO vehicle isadded, and samples gently mixed. All assays are performed in triplicate.Samples are then incubated for 5 or 15 minutes at 37° C., prior to theaddition of arachidonic acid. Arachidonic acid (peroxide-free, CaymanChemical) is prepared as a 10 mM stock solution in ethanol and furtherdiluted 10-fold in HBSS. An aliquot of 10 μL of this diluted solution isadded to the cells to give a final arachidonic acid concentration of 10μM. Control samples are incubated with ethanol vehicle instead ofarachidonic acid. Samples are again gently mixed and incubated for afurther 10 min. at 37° C. For osteosarcoma cells, reactions are thenstopped by the addition of 100 μL of 1N HCl, with mixing and by therapid removal of the solution from cell monolayers. For U-937 cells,reactions are stopped by the addition of 100 μL of 1N HCl, with mixing.Samples are then neutralized by the addition of 100 μL of 1N NaOH andPGE₂ levels measured by radioimmunoassay.

Whole cell assays for COX-2 and COX-1 using CHO transfected cell lines

Chinese hamster ovary (CHO) cell lines which have been stablytransfected with an eukaryotic expression vector pCDNAIII containingeither the human COX-1 or COX-2 cDNA's are used for the assay. Thesecell lines are referred to as CHO hCOX-1! and CHO hCOX-2!, respectively.For cyclooxygenase assays, CHO hCOX-1! cells from suspension culturesand CHO hCOX-2! cells prepared by trypsinization of adherent culturesare harvested by centrifugation (300×g, 10 min) and washed once in HBSScontaining 15 mM HEPES, pH 7.4, and resuspended in HBSS, 15 mM HEPES, pH7.4, at a cell concentration of 1.5×10⁶ cells/ml. Drugs to be tested aredissolved in DMSO to 66.7-fold the highest test drug concentration.Compounds are typically tested at 8 concentrations in duplicate usingserial 3-fold serial dilutions in DMSO of the highest drugconcentration. Cells (0.3×10⁶ cells in 200 μl) are preincubated with 3μl of the test drug or DMSO vehicle for 15 min at 37° C. Workingsolutions of peroxide-free AA (5.5 μM and 110 μM AA for the CHO hCOX-1!and CHO COX-2! assays, respectively) are prepared by a 10-fold dilutionof a concentrated AA solution in ethanol into HBSS containing 15 mMHEPES, pH 7.4. Cells are then challenged in the presence or absence ofdrug with the AA/HBSS solution to yield a final concentration of 0.5 μMAA in the CHO hCOX-1! assay and a final concentration of 10 μM AA in theCHO hCOX-2! assay. The reaction is terminated by the addition of 10 μl1N HCl followed by neutralization with 20 μl of 0.5N NaOH. The samplesare centrifuged at 300×g at 4° C. for 10 min, and an aliquot of theclarified supernatant is appropriately diluted for the determination ofPGE₂ levels using an enzyme-linked immunoassay for PGE₂ (Correlate PGE₂enzyme immunoassay kit, Assay Designs, Inc.). Cyclooxygenase activity inthe absence of test compounds is determined as the difference in PGE₂levels of cells challenged with arachidonic acid versus the PGE₂ levelsin cells mock-challenged with ethanol vehicle. Inhibition of PGE₂synthesis by test compounds is calculated as a percentage of theactivity in the presence of drug versus the activity in the positivecontrol samples.

Assay of COX-1 Activity from U937 cell microsomes

U 937 cells are pelleted by centrifugation at 500×g for 5 min and washedonce with phosphate-buffered saline and repelleted. Cells areresuspended in homogenization buffer consisting of 0.1M Tris-HCl, pH7.4, 10 mM EDTA, 2 μg/ml leupeptin, 2 μg/ml soybean trypsin inhibitor, 2μg/ml aprotinin and 1 mM phenyl methyl sulfonyl fluoride. The cellsuspension is sonicated 4 times for 10 sec and is centrifuged at10,000×g for 10 min at 4° C. The supernatant is centrifuged at 100,000×gfor 1 hr at 4° C. The 100,000×g microsomal pellet is resuspended in 0.1MTris-HCl, pH 7.4, 10 mM EDTA to approximately 7 mg protein/ml and storedat -80° C.

Microsomal preparations are thawed immediately prior to use, subjectedto a brief sonication, and then diluted to a protein concentration of125 μg/ml in 0.1M Tris-HCl buffer, pH 7.4 containing 10 mM EDTA, 0.5 mMphenol, 1 mM reduced glutathione and 1 μM hematin. Assays are performedin duplicate in a final volume of 250 μl. Initially, 5 μl of DMSOvehicle or drug in DMSO are added to 20 μl of 0.1M Tris-HCl buffer, pH7.4 containing 10 mM EDTA in wells of a 96-deepwell polypropylene titreplate. 200 μl of the microsomal preparation are then added andpre-incubated for 15 min at room temperature before addition of 25 μl of1M arachidonic acid in 0.1M Tris-HCl and 10 mM EDTA, pH 7.4. Samples areincubated for 40 min at room temperature and the reaction is stopped bythe addition of 25 μl of 1N HCl. Samples are neutralized with 25 μl of1N NaOH prior to quantitation of PGE₂ content by radioimmunoassay(Dupont-NEN or Amersham assay kits). Cyclooxygenase activity is definedas the difference between PGE₂ levels in samples incubated in thepresence of arachidonic acid and ethanol vehicle.

Assay of the activity of purified human COX-2

The enzyme activity is measured using a chromogenic assay based on theoxidation of N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) during thereduction of PGG₂ to PGH₂ by COX-2 (Copeland et al. (1994) Proc. Natl.Acad. Sci. 91, 11202-11206).

Recombinant human COX-2 is purified from Sf9 cells as previouslydescribed (Percival et al (1994) Arch. Biochem. Biophys. 15, 111-118).The assay mixture (180 μL) contains 100 mM sodium phosphate, pH 6.5, 2mM genapol X-100, 1 μM hematin, 1 mg/ml gelatin, 80-100 units ofpurified enzyme (One unit of enzyme is defined as the amount of enzymerequired to produce an O.D. change of 0.001/min at 610 nm) and 4 μL ofthe test compound in DMSO. The mixture is pre-incubated at roomtemperature (22° C.) for 15 minutes prior to initiation of the enzymaticreaction by the addition of 20 μL of a sonicated solution of 1 mMarachidonic acid (AA) and 1 mM TMPD in assay buffer (without enzyme orhematin). The enzymatic activity is measured by estimation of theinitial velocity of TMPD oxidation over the first 36 sec of thereaction. A non-specific rate of oxidation is observed in the absence ofenzyme (0.007-0.010 O.D./min) and is subtracted before the calculationof the % inhibition. IC₅₀ values are derived from 4-parameter leastsquares non-linear regression analysis of the log-dose vs % inhibitionplot.

HUMAN WHOLE BLOOD ASSAY

Rationale

Human whole blood provides a protein and cell-rich milieu appropriatefor the study of biochemical efficacy of anti-inflammatory compoundssuch as selective COX-2 inhibitors. Studies have shown that normal humanblood does not contain the COX-2 enzyme. This is consistent with theobservation that COX-2 inhibitors have no effect on PGE₂ production innormal blood. These inhibitors are active only after incubation of humanwhole blood with LPS, which induces COX-2. This assay can be used toevaluate the inhibitory effect of selective COX-2 inhibitors on PGE₂production. As well, platelets in whole blood contain a large amount ofthe COX-1 enzyme. Immediately following blood clotting, platelets areactivated through a thrombin-mediated mechanism. This reaction resultsin the production of thromboxane B₂ (TxB₂) via activation of COX-1.Thus, the effect of test compounds on TxB₂ levels following bloodclotting can be examined and used as an index for COX-1 activity.Therefore, the degree of selectivity by the test compound can bedetermined by measuring the levels of PGE₂ after LPS induction (COX-2)and TxB₂ following blood clotting (COX-1) in the same assay.

Method

A. COX-2 (LPS-induced PGF₂ production)

Fresh blood is collected in heparinized tubes by venipuncture from bothmale and female volunteers. The subjects have no apparent inflammatoryconditions and have not taken any NSAIDs for at least 7 days prior toblood collection. Plasma is immediately obtained from a 2 mL bloodaliquot to use as blank (basal levels of PGE₂). The remaining blood isincubated with LPS (100 μg/ml final concentration, Sigma Chem, #L-2630from E. coli; diluted in 0.1% BSA (Phosphate buffered saline) for 5minutes at room temperature. Five hundred μL aliquots of blood areincubated with either 2 μL of vehicle (DMSO) or 2 μL of a test compoundat final concentrations varying from 10 nM to 30 μM for 24 hours at 37°C. At the end of the incubation, the blood is centrifuged at 12,000×gfor 5 minutes to obtain plasma. A 100 μL aliquot of plasma is mixed with400 μL of methanol for protein precipitation. The supernatant isobtained and is assayed for PGE₂ using a radioimmunoassay kit (Amersham,RPA#530) after conversion of PGE₂ to its methyl oximate derivativeaccording to the manufacturer's procedure.

B. COX-1 (Clotting-induced TxB₂ production)

Fresh blood is collected into vacutainers containing no anticoagulants.Aliquots of 500 μL are immediately transferred to siliconizedmicrocentrifuge tubes preloaded with 2 μL of either DMSO or a testcompound at final concentrations varying from 10 nM to 30 μM. The tubesare vortexed and incubated at 37° C. for 1 hour to allow blood to clot.At the end of incubation, serum is obtained by centrifugation (12,000×gfor 5 min.). A 100 μL aliquot of serum is mixed with 400 μL of methanolfor protein precipitation. The supernatant is obtained and is assayedfor TxB₂ using a enzyme immunoassay kit (Cayman, #519031) according tothe manufacturer's instruction.

RAT PAW EDEMA ASSAY

Protocol

Male Sprague-Dawley rats (150-200 g) are fasted overnight and are given,po, either vehicle (1% methocel or 5% Tween 80) or a test compound. Onehr later, a line is drawn using a permanent marker at the level abovethe ankle in one hind paw to define the area of the paw to be monitored.The paw volume (V₀) is measured using a plethysmometer (Ugo-Basile,Italy) based on the principle of water displacement. The animals arethen injected subplantarly with 50 μl of 1% carrageenan solution insaline (FMC Corp, Maine) into the paw using an insulin syringe with a25-gauge needle (i.e. 500 μg carrageenan per paw). Three hr later, thepaw volume (V₃) is measured and the increases in paw volume (V₃ -V₀) arecalculated. The animals are sacrificed by CO₂ asphyxiation and theabsence or presence of stomach lesions scored. Data is compared with thevehicle-control values and percent inhibition calculated. All treatmentgroups are coded to eliminate observer bias.

NSAID-INDUCED GASTROPATHY IN RATS

Rationale

The major side effect of conventional NSAIDs is their ability to producegastric lesions in man. This action is believed to be caused byinhibition of Cox-1 in the gastrointestinal tract. Rats are particularlysensitive to the actions of NSAIDs. In fact, rat models have been usedcommonly in the past to evaluate the gastrointestinal side effects ofcurrent conventional NSAIDs. In the present assay, NSAID-inducedgastrointestinal damage is observed by measuring fecal ⁵¹ Cr excretionafter systemic injection of ⁵¹ Cr-labeled red blood cells. Fecal ⁵¹ Crexcretion is a well-established and sensitive technique to detectgastrointestinal integrity in animals and man.

Methods

Male Sprague Dawley rats (150-200 g) are administered orally a testcompound either once (acute dosing) or b.i.d. for 5 days (chronicdosing). Immediately after the administration of the last dose, the ratsare injected via a tail vein with 0.5 mL of ⁵¹ Cr-labeled red bloodcells from a donor rat. The animals are placed individually inmetabolism cages with food and water ad lib. Feces are collected for a48 h period and ⁵¹ Cr fecal excretion is calculated as a percent oftotal injected dose. ⁵¹ Cr-labeled red blood cells are prepared usingthe following procedures. Ten mL of blood is collected in heparinizedtubes via the vena cava from a donor rat. Plasma is removed bycentrifugation and replenished with equal volume of HBSS. The red bloodcells are incubated with 400 Ci of sodium 51chromate for 30 min. at 37C. At the end of the incubation, the red blood cells are washed twicewith 20 mL HBSS to remove free sodium ⁵¹ chromate. The red blood cellsare finally reconstituted in 10 mL HBSS and 0.5 mL of the solution(about 20 Ci) is injected per rat.

PROTEIN-LOSING GASTROPATHY IN SQUIRREL MONKEYS

Rationale

Protein-losing gastropathy (manifested as appearance of circulatingcells and plasma proteins in the GI tract) is a significant anddose-limiting adverse response to standard non-steroidalantiinflammatory drugs (NSAIDs). This can be quantitatively assessed byintravenous administration of ⁵¹ CrCl₃ solution. This isotopic ion canavidly bind to cell and serum globins and cell endoplasmic reticulum.Measurement of radioactivity appearing in feces collected for 24 h afteradministration of the isotope thus provides a sensitive and quantitativeindex of protein-losing gastropathy.

Methods

Groups of male squirrel monkeys (0.8 to 1.4 kg) are treated by gavagewith either 1% methocell or 5% Tween 80 in H₂ O vehicles, (3 mL/kgb.i.d.) or test compounds at doses from 1-100 mg/kg b.i.d. for 5 days.Intravenous ⁵¹ Cr (5 Ci/kg in 1 ml/kg phosphate buffer saline (PBS)) isadministered 1 h after the last drug/vehicle dose, and feces collectedfor 24 h in a metabolism cage and assessed for excreted ⁵¹ Cr bygamma-counting. Venous blood is sampled 1 h and 8 h after the last drugdose, and plasma concentrations of drug measured by RP-HPLC.

RAT PLASMA LEVELS

Per Os Pharmacokinetics in Rats

PROCEDURE

The animals are housed, fed and cared for according to the Guidelines ofthe Canadian Council on Animal Care.

Male Sprague Dawley rats (325-375 g) are fasted overnight prior to eachPO blood level study.

The rats are placed in the restrainer one at a time and the box isfirmly secured. The zero blood sample is obtained by nicking a small (1mm or less) piece off the tip of the tail. The tail is then stroked witha firm but gentle motion from the top to the bottom to milk out theblood. Approximately 1 mL of blood is collected into a heparinizedvacutainer tube.

Compounds are prepared as required, in a standard dosing volume of 10mL/kg, and administered orally by passing a 16 gauge, 3" gavaging needleinto the stomach.

Subsequent bleeds are taken in the same manner as the zero bleed exceptthat there is no need to nick the tail again. The tail is cleaned with apiece of gauze and milked/stroked as described above into theappropriately labelled tubes.

Immediately after sampling, blood is centrifuged, separated, put intoclearly marked vials and stored in a freezer until analysed.

Typical time points for determination of rat blood levels after POdosing are:

0, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h

After the 4 hr time point bleed, food is provided to the rats adlibitum. Water is provided at all times during the study.

Vehicles

The following vehicles may be used in PO rat blood level determinations:

PEG 200/300/400--restricted to 2 mL/kg

Methocel 0.5%-1.0% 10 mL/kg

Tween 80 5% 10 mL/kg

Compounds for PO blood levels can be in suspension form. For betterdissolution, the solution can be placed in a sonicator for approximately5 minutes.

Intravenous Pharmacokinetics in Rats

PROCEDURE

The animals are housed, fed and cared for according to the Guidelines ofthe Canadian Council on Animal Care.

Male Sprague Dawley (325-375 g) rats are placed in plastic shoe boxcages with a suspended floor, cage top, water bottle and food.

The compound is prepared as required, in a standard dosing volume of 1mL/kg.

Rats are bled for the zero blood sample and dosed under CO₂ sedation.The rats, one at a time, are placed in a primed CO₂ chamber and takenout as soon as they had lost their righting reflex. The rat is thenplaced on a restraining board, a nose cone with CO₂ delivery is placedover the muzzle and the rat restrained to the board with elastics. Withthe use of forceps and scissors, the jugular vein is exposed and thezero sample taken, followed by a measured dose of compound which isinjected into the jugular vein. Light digital pressure is applied to theinjection site, and the nose cone was removed. The time is noted. Thisconstituted the zero time point.

The 5 min bleed is taken by nicking a piece (1-2 mm) off the tip of thetail. The tail is then stroked with a firm but gentle motion from thetop of the tail to the bottom to milk the blood out of the tail.Approximately 1 mL of blood is collected into a heparinized collectionvial. Subsequent bleeds are taken in the same fashion, except that thereis no need to nick to tail again. The tail is cleaned with a piece ofgauze and bled, as described above, into the appropriate labelled tubes.

Typical time points for determination of rat blood levels after I.V.dosing are either:

0, 5 min, 15 min, 30 min, 1 h, 2 h, 6 h

or

0, 5 min, 30 min, 1 h, 2 h, 4 h, 6 h.

Vehicles

The following vehicles may be used in IV rat blood level determinations:

Dextrose: 1 mL/kg

Molecusol 25%: 1 mL/kg

DMSO: (Dimethylsulfoxide) Restricted to a dose volume of 0.1 mL peranimal

PEG 200: Not more than 60% mixed with 40% sterile water-1 mL/kg

With Dextrose, either sodium bicarbonate or sodium carbonate can beadded if the solution is cloudy.

For analysis, aliquots are diluted with an equal volume of acetonitrileand centrifuged to remove protein precipitate. The supernatant isinjected directly onto a C-18 HPLC column with UV detection.Quantitation is done relative to a clean blood sample spiked with aknown quantity of drug. Bioavailability (F) is assessed by comparingarea under the curve (AUC) i.v. versus p.o. ##EQU1## Clearance rates arecalculated from the following relation: ##EQU2## The units of Cl aremL/h.kg (milliliters per hour kilogram)

Representative Biological Data

Compounds of the present invention are prodrugs of inhibitors of COX-2and are thereby useful in the treatment of COX-2 mediated diseases asenumerated above. The extent of conversion of these compounds to theactive COX-2 inhibitors may be seen in the representative results shownbelow along with their antiinflammatory activity. The plasma levelsindicated are the maximum rat plasma concentrations of the active COX-2inhibitor observed when the rat was treated with a 20 mg/kg oral dose ofthe indicated prodrug. The ED₅₀ values in the rat paw edema assayrepresent the dose of prodrug required to reduce edema formation by 50%as compared to the vehicle control.

                  TABLE 2                                                         ______________________________________                                                                 Rat Paw Edema                                        Example    Plasma Levels (μM)*                                                                      (ED.sub.50, mg/kg)                                   ______________________________________                                        1          7.5           2.5                                                  2          3.9           0.7                                                  9          0.7           1.7                                                  10         16            0.09                                                 13         27            0.9                                                  39         18            2.7                                                  40         45            1.5                                                  44         4.6           1.6                                                  ______________________________________                                         *Maximum plasma concentration of the corresponding carbonyl compound          observed in rats when dosed at 20 mg/kg orally with the indicated prodrug                                                                              

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) all operations were carried out at room or ambient temperature, thatis, at a temperature in the range 18°-25° C.;

(ii) evaporation of solvent was carded out using a rotary evaporatorunder reduced pressure (600-4000 pascals: 4.5-30 mm Hg) with a bathtemperature of up to 60° C.;

(iii) the course of reactions was followed by thin layer chromatography(TLC) and reaction times are given for illustration only;

(iv) melting points are uncorrected and d' indicates decomposition; themelting points given are those obtained for the materials prepared asdescribed; polymorphism may result in isolation of materials withdifferent melting points in some preparations;

(v) the structure and purity of all final products were assured by atleast one of the following techniques: TLC, mass spectrometry, nuclearmagnetic resonance (NMR) spectrometry or microanalytical data;

(vi) yields are given for illustration only;

(vii) when given, NMR data is in the form of delta (δ) values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as internal standard, determined at 300 MHz or400 MHz using the indicated solvent; conventional abbreviations used forsignal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br.broad; etc.: in addition "Ar" signifies an aromatic signal;

(viii) chemical symbols have their usual meanings; the followingabbreviations have also been used v (volume), w (weight), b.p. (boilingpoint), M.P. (melting point), L (liter(s)), mL (milliliters), g(gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq(equivalent(s)).

EXAMPLE 15,5-Dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran(Method A)

Step 1 2-Hydroxy-4'-(methylsulfonyl)isobutyrophenone

To a solution of 2-hydroxy-4'-(methylthiol)isobutyrophenone (J. Org.Chem. 56, 5955-8, 1991) (45 g) in t-BuOH (500 mL) and CH₂ Cl₂ (200 mL)was added a solution of OXONE™ (194 g) in H₂ O (1.4 L). The reactionmixture was stirred for 18 h at r.t. and then extracted with EtOAc(3×500 mL). The organic extracts were combined and dried over Na₂ SO₄and the solvent was evaporated. The residue was swished in ether/hexaneto give the title compound as a yellow solid (47.4 g).

Step 2 3-Fluorophenylacetic acid,1,1-dimethyl-2-(4-(methylsulfonyl)phenyl)-2-oxo-ethyl ester

A mixture of 2-hydroxy-4'-(methylsulfonyl)isobutyrophenone (100 g),3-fluorophenylacetic acid (83 g),1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate(225 g) and DMAP (25 g) in CH₂ Cl₂ (2 L) was mechanically stirred for 17h at r.t. A solution of 1M HCl (1 L) was then added and the organicphase was separated, washed with a saturated solution of Na₂ CO₃ (0.4 L)and dried over MgSO₄. After concentration, the residue was purified bysilica gel chromatography, eluting with 30% EtOAc/hexanes to give thetitle compound as a white solid (133 g).

Step 35,5-Dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

A solution of the product from Step 2 (120 g) in CH₂ Cl₂ (1 L) wastreated with DBU (81.6 g) and stirred for 1 h at r.t. The reactionmixture was then treated with 1M HCl (550 mL) and the organic phase wasseparated, washed with saturated NaHCO₃ and dried over MgSO₄. Afterconcentration, the crude was swished from 20% EtOAc/hexanes (450 mL) togive the title compound as a white solid (108.4 g, m.p. 172.7° C.).

Step 45,5-Dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran

To a -50° C. solution of5,5-dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone(30 g, 83.3 mmol) in 500 mL of THF was added dropwise a solution ofDIBAL (90 mL, 1.5M in toluene) over a period of 15 min. The reactionmixture was allowed to warm to -10° C. over a period of 1 h, thentreated with 20 mL of acetone, followed by 50 mL of methanol. Thereaction mixture was then warmed to -20° C. and treated with aqueouspotassium sodium tartrate (20%, 400 mL). After stirring at r.t. for 1 h,the product was extracted with 500 mL of 2:1 EtOAc/hexane, dried overNa₂ SO₄, filtered and concentrated. The crude product was swished with2:1 hexane/EtOAc to give 24 g of purified title compound as a whitesolid.

¹ H NMR (CD₃ COCD₃) δ 8.00 (2H, d), 7.55 (2H, d), 7.20 (1H, m), 7.04(1H, m), 7.02 (1H, s), 6.93 (1H, m), 6.29 (1H, d), 5.60 (1H, d), 3.15(3H, s), 1.48 (3H, s), 1.36 (3H, s)

The following examples were prepared according to the indicated methodin each case.

EXAMPLE 23-(3,5-Difluorophenyl)-5,5-dimethyl-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Method A)

¹ H NMR (CD₃ COCD₃) δ 8.01 (2H, d), 7.56 (2H, d), 6.9-6.8 (3H, m), 6.29(1H, d), 5.67 (1H, d), 3.15 (3H, s), 1.47 (3H, s), 1.37 (3H, s).

EXAMPLE 35,5-Dimethyl-3-(4-fluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Method A)

¹ H NMR (CD₃ COCD₃) δ 7.78 (2H, m), 7.44 (2H, m), 7.18 (2H, m), 6.89(2H, m), 6.35 (1H, s), 3.11 (3H, s), 1.42 (3H, s), 1.36 (3H, s).

EXAMPLE 45,5-Dimethyl-3-(4-fluorophenyl)-2-methoxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Method B)

¹ H NMR (CD₃ COCD₃) δ 7.78 (2H, m), 7.52 (2H, m), 7.22 (2H, m), 6.95(2H, m), 6.00 (1H, s), 3.45 (3H, s), 3.14 (3H, s), 1.46 (3H, s), 1.35(3H, s).

EXAMPLE 55,5-Dimethyl-2-ethoxy-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Method B)

To a solution of5,5-dimethyl-2-hydroxy-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Example 1, 500 mg, 1.38 mmol) in 5 mL of EtOH was added 3 drops ofBF₃.OEt₂. The mixture was stirred at room temperature for 45 min, andthe resulting precipitate was filtered and washed with EtOH to provide497 mg of the title compound as a white solid.

¹ H NMR (CD₃ COCD₃) δ 8.00 (2H, m), 7.55 (2H, m), 7.20 (1H, m), 6.98(3H, m), 6.10 (1H, s), 3,85 (1H, m), 3.70 (1H, m), 3.15 (3H, s), 1.50(3H, s), 1.35 (3H, s), 1.20 (3H, t).

EXAMPLE 65,5-Dimethyl-3-(3-fluorophenyl)-2-isopropoxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Method B)

¹ H NMR (CD₃ COCD₃) δ 7.95 (2H, m), 7.50 (2H, m), 7.18 (1H, m), 6.93(3H, m), 6.15 (1H, s), 4.13 (1H, m), 3.15 (3H, s), 1.50 (3H, s), 1.35(3H, s), 1.25 (3H, d), 1.20 (3H, d).

EXAMPLE 75,5-Dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-methylthio-2,5-dihydrofuran(Method B)

¹ H NMR (CD₃ COCD₃) δ 7.95 (2H, d), 7.52 (2H, d), 7.21 (1H, m), 6.95(3H, m), 6.53 (1H, s), 3.13 (3H, s), 2.12 (3H, s), 1.61 (3H, s)

EXAMPLE 85-Ethyl-3-(4-fluorophenyl)-2-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Method A)

¹ H NMR (CD₃ COCD₃) δ 7.98 (2H, d), 7.53 (2H, d), 7.17 (1H, m), 7.02(2H, m), 6.94 (1H, m), 6.36 (1H, d), 5.67 (1H, d), 3.14 (3H, s), 1.72(1H, m), 1.60 (1H, m), 1.35 (3H, s), 1.04 (3H, t).

EXAMPLE 95,5-Dimethyl-3-(3-fluorophenoxy)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Method E)

Analysis: Calc. for C₁₉ H₁₉ FO₅ S: C, 60.31; H, 5.06; S, 8.47. Found: C,60.24; H, 5.16; S, 8.34.

EXAMPLE 105,5-Dimethyl-3-(3,4-difluorophenoxy)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Method E)

Step 13-(3,4-Difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

A solution of 3,4-difluorophenoxyacetic acid (0.51 g, 2.73 mmol),2-hydroxy-4'-(methylsulfonyl)isobutyrophenone (Ex. 1, Step 1, 0.5 g, 2.1mmol), CMC (1.13 g, 2.73 mmol) and DMAP (15 mg, 0.10 mmol) indichloromethane (12 mL) was stirred at r.t. for 18 hrs. DBU (0.63 ml,4.2 mmol) was then added and the reaction mixture was heated to refluxfor 3 hrs. After cooling to r.t., the mixture was extracted with ethylacetate and washed successively with water, 1N HCl and brine. Theorganic layer was dried over MgSO₄, filtered and concentrated. Theresidue was triturated with a mixture of ethyl acetate and hexane toafford the title compound as a solid. m.p.: 93°-95° C.

¹ H NMR (CD₃ COCD₃) ∂ 1.77 (6H, s), 3.15 (3H, s), 6.93-6.97 (1H, m),7.12-7.29 (2H, m), 7.92 (2h, d), 8.04 (2H, d).

Analysis calculated for C₁₉ H₁₆ F₂ O₅ S: C, 57.86; H, 4.09. Found: C,57.77; H, 4.28

Step 25,5-Dimethyl-3-(3,4-difluorophenoxy)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran

To a 0° C. solution of3-(3,4-difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one(500 mg, 1.27 mmol) in 10 mL of THF was added DIBAL (1.5M in toluene,2.8 mL, 4.2 mmol). Warmed to r.t. and stirred 30 min. The reaction wasquenched with acetone, followed by 0.5M sodium potassium tartrate andstirred overnight. The mixture was extracted with EtOAc, washed withbrine, dried over MgSO₄, filtered and concentrated. Crystalization fromCH₂ Cl₂ /toluene provided 350 mg of the title compound.

¹ H NMR (CD₃ COCD₃) δ 7.91 (2H, d), 7.68 (2H, d), 7.07-7.12 (2H, m),6.92-6.97 (1H, m), 5.90 (1H, d), 5.69 (1H, d), 3.09 (3H, s), 1.59 (3H,s), 1.46 (3H, s). m.p. 151° C. Analysis: Calc. for C₁₉ H₁₈ F₂ O₅ S: C,57.57; H, 4.58. Found: C, 57.42; H, 4.67.

EXAMPLE 113-(3,4-Difluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Method A) EXAMPLE 122-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-ol(Method A)

¹ H NMR (CD₃ COCD₃) δ 7.75 (2H, d), 7.32 (2H, d), 7.24-7.16 (2H, m),6.99-6.95 (2H, m), 5.18 (1H, br s), 3.12-3.00 (1H, m), 3.02 (3H, s),2.74 (1H, m), 2.51 (1H, m), 2.00 (1H, m).

EXAMPLE 13 3-(4-(Methylsulfonyl)phenyl)-2-phenyl-2-cyclopenten-1-ol(Method A)

¹ H NMR (CD₃ COCD₃) δ 7.76 (2H, d), 7.42 (2H, d), 7.28-7.20 (5H, m),5.13 (1H, m), 4.08 (1H, d), 3.08 (3H, s), 3.05 (IH, m), 2.78 (1H, m),2.44 (1H, m), 1.95 (1H, m).

EXAMPLE 142-Acetoxy-5,5-dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(Method D)

To a solution of5,5-Dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran(Example 1, 0.8 g) and triethylamine (2 mL) in dichloromethane (20 mL)was added DMAP (5 mg) and acetic anhydride (1 mL). The resulting mixturewas stirred at room temperature for 10 min, then quenched with saturatedaqueous NaHCO₃. The mixture was extracted with CH₂ Cl₂ and the organicphase was dried over Na₂ SO₄, filtered and evaporated. The resultingsolid was swished in 1:1 EtOAc/hexanes to provide 0.5 g of the titlecompound as a white solid.

¹ H NMR (CD₃ COCD₃) δ 8.03 (2H, d), 7.60 (2H, d), 7.27 (1H, s), 7.25(1H, m), 7.00 (2H, m), 6.37 (1H, m), 3.16 (3H, s), 2.03 (3H, s), 1.55(3H, s), 1.35 (3H, s).

EXAMPLE 172-(3,5-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-ol(Method A)

Step 1 3-(4-(Methylthiol)phenyl)-2-cyclopenten-1-one

To a -65° C. solution of 4-bromothioanisole (61 g, 0.3 mol) in THF (800mL) was added a solution of n-BuLi (2.3M in hexanes, 120 mL) at a rateso as to maintain an internal temperature below -55° C. The resultingslush was stirred at -65° C. for 2 h, then treated with a solution of3-ethoxy-2-cyclopenten-1-one (35 g, 0.28 mmol) in THF (50 mL). After 30min at -65° C., the solution was warmed to 0° C. and quenched with sat.aq. NH₄ Cl (400 mL). The product was extracted with 3×1 L of EtOAc andthe combined extracts were dried over MgSO₄ and concentrated. Theresulting material was swished in 200 mL of 1:1 EtOAc/hexanes to provide45 g of the title compound as a white solid.

Step 2 2-Bromo-3-(4-(methylthiol)phenyl)-2-cyclopenten-1-one

To a suspension of 3-(4-(methylthiol)phenyl)-2-cyclopenten-1-one (9.64g, 47.2 mmol) in CCl₄ (200 mL) was added a solution of bromine (5 mL) inCCl₄ (30 mL) over 20 min. The resulting orange suspension was stirredfor 1.5 h, then cooled in an ice-bath, and triethylamine (14 mL, 100mmol) was added. After 30 min, the mixture was quenched with 1M HCl (300mL) and extracted with CH₂ Cl₂. The organic phase was washed with brine,filtered through cotton and evaporated. Purification by silica gelchromatography, eluting with 90% CH₂ Cl₂ /hexanes gave the titlecompound (7.13 g).

Step 3 2-Bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one

To a 0° C. solution of2-bromo-3-(4-(methylthiol)phenyl)-2-cyclopenten-1-one (5.73 g, 20.2mmol) in CH₂ Cl₂ (100 mL) and MeOH (50 mL) was added MMPP (19 g, 30.7mmol). The mixture was stirred 5 h at r.t., then concentrated. Theresidue was partitioned between sat. aq. NaHCO₃ and CH₂ Cl₂. The organicphase was washed with brine, filtered through cotton and evaporated. Theresulting solid was swished in CH₂ Cl₂ /hexanes to provide the titlecompound (5.57 g).

Step 42-(3,5-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one

To a mixture of 2-bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one(664 mg, 2.11 mmol), 3,5-difluorophenylboronic acid (832 mg, 5.27 mmol),tris(dibenzylideneacetone)dipalladium(0) (83 mg, 0.09 mmol), andtriphenylphosphine (96 mg, 0.36 mmol) was added 40 mL of 3:1:1toluene:n-propanol:water and the mixture was purged with nitrogen. Afterstirring 10 min, diethylamine (1.1 mL, 10.6 mmol) was added and thesolution was heated to reflux for 4 h. The mixture was cooled andpartitioned between 1M NaOH and EtOAc. The organic phase was washed withwater, 1M HCl and brine, and dried over MgSO₄. Purification by silicagel chromatography, eluting with 50% CH₂ Cl₂ /hexanes, followed bycrystallization from CH₂ Cl₂ /ether/hexanes gave the title compound (223mg).

¹ H NMR (CD₃ COCD₃) δ 7.95 (2H, d), 7.65 (2H, d), 6.98 (1H, m), 6.82(2H, m), 3.19 (2H, m), 3.15 (3H, s), 2.68 (2H, m).

Step 52-(3,5-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-ol

To a -78° C. solution of2-(3,5-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one(98 mg, 0.28 mmol) in THF (5 mL) was added DIBAL (1.5M toluene solution,0.4 mL, 0.6 mmol). The solution was warmed to 0° C. and stirred 15 min,then cooled to -78° C. and quenched with 0.5 mL acetone. The solutionwas warmed and poured into 1M sodium potassium tartrate. The mixture wasextracted with EtOAc, washed with brine, and dried over MgSO₄.Crystallization from ether/hexanes provided the title compound (90 mg).

¹ H NMR (CD₃ COCD₃) δ 7.85 (2H, d), 7.45 (2H, d), 6.85 (3H, m), 5.13(1H, m), 4.33 (d, 1H), 3.10 (3H, s), 3.02 (1H, m), 2.83 (1H, m), 2.48(1H, m), 1.95 (1H, m).

EXAMPLE 20Sodium(5,5-dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran-2-yloxy)actetate(Method B)

¹ H NMR (DMSO-d₆) δ 8.01 (2H, m), 7.60 (1H, m), 7.53 (2H, m), 7.12 (2H,m), 7.00 (1H, m), 6.35 (1H, s), 3.98 (1H, d), 3.75 (1H, d), 3.29 (3H,s), 1.38 (3H, s), 1.28 (3H, s).

EXAMPLE 21 Succinic acidmono-(3-(4-(methylsulfonyl)phenyl)-2-phenyl-cyclopent-2-enyl)ester(Method D)

¹ H NMR (CD₃ COCD₃) δ 7.80 (2H, m), 7.46 (2H, m), 7.26 (3H, m), 7.19(2H, m), 6.17 (1H, m), 3.15 (1H, m), 3.10 (3H, s), 2.86 (1H, m), 1.38(3H, s), 2.5 (5H, m), 2.0 (1H, m).

EXAMPLE 393-Isopropoxy-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol(Method A)

¹ H NMR (CD₃ COCD₃, 300 MHz) δ 7.90 (2H, m), 7.83 (2H, m), 5.96 (1H, d),5.53 (1H, d), 4.66 (1H, m), 3.12 (3H, s), 1.55 (3H, s), 1.42 (3H, s),1.25 (6H, m). Analysis: Calc. for C₁₆ H₂₂ O₅ S: C, 58.88; H, 6.79 Found:C, 58.69; H, 6.69.

EXAMPLE 40 3-(4-Methylsulfonylphenyl)-2-(3-pyridinyl)-2-cyclopenten-1-ol(Method A)

¹ H NMR (CD₃ COCD₃, 300 MHz) δ 8.46 (1H, m), 8.40 (1H, m), 7.28 (2H, m),7.59 (1H, m), 7.32 (2H, m), 7.22 (1H, m), 5.22 (1H, m), 3.10 (1H, m),3.02 (3H, s), 2.80 (1H, m), 2.56 (1H, m), 2.03 (1H, m).

EXAMPLE 415,5-Dimethyl-4-(4-methylsulfonylphenyl)-3-phenyl-2,5-dihydrofuran-2-ol(Method A)

Analysis: Calc. for C₁₉ H₂₀ O₄ S: C, 66.26; H, 5.85 Found: C, 66.19; H,6.02.

EXAMPLE 423-(3-Fluorophenyl)-5,5-dimethyl-4-(4-methylsulfinylphenyl)-2,5-dihydro-furan-2-ol(Method A)

¹ H NMR (CD₃ COCD₃, 400 MHz) δ 7.23 (2H, d), 6.95 (2H, d), 7.19(1H, m),7.04 (2H, m), 6.90 (1H, m), 6.28 (0.5H, d), 6.26 (1H, s), 5.54 (0.5H,d), 2.72 (3H, s), 1.46 (3H, s), 1.32 (3H, s).

EXAMPLE 433-(3,4-Difluorophenyl)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol(Method A)

¹ H NMR (CD₃ COCD₃, 300 MHz) δ 8.00 (2H, m), 7.55 (2H, m), 7.21 (1H, m),7.12 (1H, m), 7.03 (1H, m), 6.28 (1H, d), 5.16 (1H, d), 3.15 (3H, s),1.49 (3H, s), 1.38 (3H, s).

EXAMPLE 443-(1-Cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol(Method A)

¹ H NMR (CD₃ COCD₃, 300 MHz) δ 7.90 (4H, m), 5.95 (1H, dd), 5.50 (1H,dd), 4.00(1H, m), 3.10 (3H, s), 1.55 (3H, s), 1.40 (3H, s), 1.30 (3H,d), 0.3-1.10 (5H, m).

EXAMPLE 453-Cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol(Method A)

Analysis: Calc. for C₁₇ H₂₂ O₅ S: C, 60.34; H, 6.55 Found: C, 60.81; H,6.48. MS: 321 (M⁺ --OH).

EXAMPLE 463-(3,4-Difluorophenoxy)-5-methyl-4-(4-methylsulfonylphenyl)-5-(2,2,2-trifluoroethyl)-2,5-dihydrofuran-2-ol(Method A)

¹ H NMR (CD₃ COCD₃, 400 MHz) δ 7.95-7.70 (4H, m), 7.35-6.90 (3H, m),5.95 (1H, m), 3.10 (3H, 2s), 2.95-2.65 (4H, m), 1.75 and 1.68 (3H, 2s).MS (FAB): 464 (M⁺), 447 (M⁺ --OH).

EXAMPLE 47 4-3-(4-Methylsulfonylphenyl)-2-phenyl-cyclopent-2-enyloxycarbonylamido!benzoicacid, ethyl ester (Methods A+F)

To a solution of ethyl 4-isocyanatobenzoate (0.47 g) and pyridine (0.5mL) in 15 mL of toluene was added a solution of3-(4-(methylsulfonyl)phenyl)-2-phenyl-2-cyclopenten-1-ol (0.40 g) in 4mL of toluene. After stirring for a period of 1.5 h at room temperature,ethanol (1 Ml) was added and the reaction mixture was diluted with EtOAc(50 mL). After washing with 1M CuSO₄ (2×20 mL), the organic layer wasdried over MgSO₄ and concentrated. The residure was purified by silicagel chromatography eluted with 30% EtOAc in hexane and the product wasthen crystalized in 50 mL of 1:1 EtOAc/hexane to give the title compoundas a white solid (0.11 g).

¹ H NMR (CD₃ COCD₃, 400 MHz) δ 9.00 (1H, bs), 7.93 (2H, d), 7.82 (2H,d), 7.65 (2H, d), 7.48 (2H, d), 7.2-7.3 (5H, m), 6.24 (1H, m), 4.30 (2H,q), 3.21 (1H, m), 3.10 (3H, s), 2.87 (1H, ddd), 2.62 (1H, m), 2.11 (1H,m), 1.33 (3H, t).

EXAMPLE 48 4-3-(4-Methylsulfonylphenyl)-2-phenyl-cyclopent-2-enyloxycarbonylamido!benzoicacid (Methods A+F)

To a solution of 4-3-(4-methylsulfonylphenyl)-2-phenyl-cyclopent-2-enyloxycarbonylamido!benzoicacid, ethyl ester (0.41 g) in 11 mL of THF were added 1M LiOH (1.85 mL)and water (2 mL). After stirring for 8 days, the reaction was treatedwith NH₄ OAc buffer solution (25% w/v) and extracted with EtOAc (50 mL).The organic layer was dried over MgSO₄ and concentrated. The crudeproduct was swished in 20 mL of EtOAc to give the title compound as awhite solid.

¹ H NMR (CD₃ COCD₃, 400 MHz) δ 10.95 (1H, bs), 9.00 (1H, bs), 7.97 (2H,d), 7.81 (1H, d), 7.64 (2H, d), 7.48 (2H, d), 7.25 (5H, m), 6.26 (1H,m), 3.20 (1H, m), 3.13 (3H, s), 2.90 (1H, ddd), 2.63 (1H, m), 2.05-2.18(1H, m).

The following section provides example for the preparation of startingmaterials for the preparation of compounds within the scope of theinvention. As appreciated by those of skill in the art, the followingsection is a self-contained unit. Thus, while the section may containExample numbers and other designations which duplicate those used forthe compounds of the instant invention, such duplication is not to beregarded as an assertion that the Examples and designations areidentical.

Starting materials for the preparation of compounds of the presentinvention can be prepared according to the following methods

Method A

An appropriately substituted acid halide is reacted with thioanisole ina solvent such as chloroform in the presence of a Lewis acid such asaluminum chloride to afford a ketone which is then hydroxylated withbase such as aqueous sodium hydroxide in a solvent such as carbontetrachloride with a phase transfer agent such as Aliquat 336. Thentreatment with an oxidizing agent such as MMPP in solvents such as CH₂Cl₂ /MeOH, affords an sulfone which is reacted with an appropriatelysubstituted acetic acid in a solvent such as CH₂ Cl₂ in the presence ofan esterifying agent such as CMC and DMAP and then treated with DBU toafford lactone Ia. ##STR54## Method B

An appropriately substituted hydroxyketone is acylated withinappropriately substituted acid halide in a solvent such asdichloromethane in the presence of a base such as pyridine. The esterobtained is then reacted with an appropriately substituted nucleophileR² XH in a solvent such as DMF and with a base such as sodium hydride,then treatment with DBU in a solvent such as acetonitrile affordslactone Ia. ##STR55## Method C

A halo ester of acetic acid is coupled with an appropriately substitutednucleophile in water with sodium hydroxide to give an appropriatelysubstituted acetic acid which is then reacted as in method A to affordlactone Ia. ##STR56## Method D

A halo ester is reacted with an appropriately substituted amine R² R¹⁵NH in a solvent such as toluene to give an intermediate which is thenreacted with DBU in a solvent such as acetonitrile to afford lactone Ia.##STR57## Method E

An appropriately substituted bromoketone is reacted with anappropriately substituted acid in a solvent such as ethanol oracetonitrile in the presence of a base such as diisopropylethylamine ortriethylamine to afford an ester which is then treated with DBU in asolvent such as acetonitrile to afford lactone Ia. ##STR58## Method F

An appropriately substituted hydroxyketone is reacted with anappropriately substituted acid halide in a solvent such asdichloromethane and with a base such as pyridine to afford an esterwhich is then cyclized using sodium hydride in a mixture of THF and DMFto afford a lactone. The lactone is then oxidized with an oxidizingagent such as MMPP, mCPBA or OXONE® in solvents such as dichloromethaneand/or methanol to afford lactone Ia. ##STR59## Method G

An appropriately substituted hydroxyketone is acylated with acetylbromide or chloride in a solvent such as dichloromethane with a basesuch as DBU and DMAP. Further treatment with a base such as sodiumhydride in a solvent such as DMF effects cyclization to afford the5-membered lactone. Treatment of this lactone with a base such as LDAand an appropriately substituted acid halide in a solvent such as THF,followed by oxidation with a reagent such as MMPP in solvent such as CH₂Cl₂ /MeOH and hydrolysis by a base such as NaOH in a solvent such asMeOH/THF gives an alcohol Ib which is then oxidized to lactone Ic by areagent such as Jone's reagent in a solvent such as acetone (theinitially formed ketone is reduced in the reaction and acylated, thusrequiring hydrolysis and re-oxidation to obtain ketone Ic).Alternatively, alcohol Ib can be obtained by using an aldehyde R² CHO asthe electrophile instead of an acid halide. ##STR60## Method H

An appropriately substituted methyl sulfide is oxidized to the sulfoxidewith a reagent such as MMPP in solvents such as dichloromethane andmethanol followed by treatment with trifluoroacetic anhydride, thenaqueous sodium hydroxide. Further treatment by Cl₂ in aqueous aceticacid followed by treatment by an amine affords an intermediatesulfonamide. This sulfonamide is then esterified with an appropriatelysubstituted acid in the presence of a reagent such as CMC and furthertreatment with a base such as DBU affords the lactone. In the case wherethe amine group is protected by an acid labile group treatment with anacid such as trifluoroacetic acid in a solvent such as dichloromethaneaffords compound Ia. ##STR61## Method I

An appropriately substituted bromoketone is reacted with anappropriately substituted acid in a solvent such as acetonitrile andwith a base such as Et₃ N. Treatment with DBU and then O₂ gives ahydroxy compound Id. Etherification of this hydroxy with an alcohol in asolvent such as THF and with an acid such HCl gives Ie. By oxidation ofthe sulfide into a sulfone by a reagent such as m-CPBA and thendisplacement of this sulfone by an appropriately substituted nucleophilecompound If is obtained. ##STR62## METHOD J

An appropriately substituted nucleophile is reacted with anappropriately substituted haloacetate in a solvent such as acetonitrilewith a base such as DBU to afford compound Ia. ##STR63## Method K

An appropriately substituted vinyl ketone is coupled with anappropriately substituted benzaldehyde with a catalyst such as3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride in the presenceof a base such as triethylamine in a solvent such as 1,4-dioxane to forma diketone. The diketone is cyclized in a solvent such as methanol witha base such as DBU to the final product Ig. When R¹ =SO₂ Me, thestarting material can also be a p-methylthiobenzaldehyde, with themethylthio group being oxidized to SO₂ Me using MMPP, mCPBA or OXONE® inthe last step. ##STR64##

EXAMPLE 13-(3,4-Difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Step 1: 2-Methyl-1-(4-(methylthio)phenyl)-propan-1-one

To a suspension of aluminum chloride (136 g, 1.02 mol) in chloroform(1.0 L) cooled to -10° C., was added dropwise isobutyrylchloride (115mL, 1.10 mol). Then thioanisole (100 mL, 0.85 mol) was added dropwise.Upon completion of addition the reaction was allowed to proceed at r.t.for 1.5 h. The reaction was cooled to 10° C. and quenched by addition ofwater (750 mL). The organic layer was separated, washed with water(2×500 mL), saturated NaHCO₃ solution (2×500 mL), brine (1×500 mL), andthen dried over Na₂ SO₄. After concentration in vacuo., the resultingcrude product crystallized upon standing under high vacuum for 30 min togive the title compound as a brown solid.

Step 2: 2-Hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one

To a solution of 2-methyl-1-(4-(methylthio)phenyl)propan-1-one (28.5 g,147 mmol, Step 1), Aliquat 336 (11.0 mL, 24 mmol) and carbontetrachloride (21 mL, 218 mmol) in toluene (43 mL) was added sodiumhydroxide (12.9 g, pellets, 322 mmol). The reaction was stirred at 15°C. for 2 h and then at r.t. for 16 h. The reaction was diluted withwater (100 mL), brine (100 mL) and EtOAc (300 mL). The aqueous phase wasacidified with 1N HCl and extracted with EtOAc (100 mL). The combinedorganic layers were dried over Na₂ SO₄ and concentrated. The crudeproduct was purified by silica gel chromatography eluted with 15% EtOAcin hexane to give the title compound as a thick syrup.

Step 3: 2-Hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl)propan-1-one

To a cold (4° C.) solution of2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (45.0 g, 214mmol, Step 2) in t-butanol (500 mL) and CH₂ Cl₂ (500 mL) was added asolution of OXONE™ (194 g, 316 mmol) in water (1.4 L). The resultingsuspension was stirred at r.t. for 18 h. The reaction was diluted withEtOAc (400 mL) and the layers were separated. The aqueous layer wasextracted with EtOAc (2×250 mL). The combined organic layers were driedover Na₂ SO₄ and concentrated in vacuo. The crude product was dissolvedin diethyl ether (250 mL), hexane was added (150 mL) and the product wasswished for 2 h. The product was collected by filtration to give thetitle compound as a yellow solid.

Step 4:3-(3,4-Difluorophenoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one

A solution of 3,4-difluorophenoxyacetic acid (0.51 g, 2.73 mmol),2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one (0.5 g, 2.1mmol, Step 3), CMC (1.13 g, 2.73 mmol) and DMAP (15 mg, 0.10 mmol) indichloromethane (12 ml) was stirred at r.t. for 18 hrs. Then, DBU (0.63ml, 4.2 mmol) was added and the reaction mixture was refluxed for 3 h.After cooling to r.t. the mixture was extracted with ethyl acetate andwashed successively with water, 1N HCl and brine. The organic layer wasdried over MgSO₄, filtered and the solvent evaporated under vacuum. Theresidue was triturated in a mixture of ethyl acetate and hexaneaffording the title compound as a solid. M.P.: 93°-95° C.

¹ H NMR (CD₃ COCD₃) ∂ 1.77 (6H, s), 3.15 (3H, s), 6.93-6.97 (1H, m),7.12-7.29 (2H, m), 7.92 (2H, d), 8.04 (2H, d).

Analysis calculated for C₁₉ H₁₆ F₂ O₅ S: C, 57.86; H, 4.09; Found: C,57.77; H, 4.28

EXAMPLE 23-(3-Fluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-on

Following the procedure described for example 1, the title compound wasprepared from 3-fluorophenoxyacetic acid. M.P.: 136°-38° C.

¹ H NMR (CD₃ COCD₃) ∂ 1.79 (6H, s), 3.15 (3H, s), 6.85-6.94 (3H, M),7.31-7.86 (1H, m), 7.93 (2H, d), 8.03 (2H,d).

EXAMPLE 33-(3,5-Difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for example 1, the title compound wasprepared from 3,5-difluorophenoxyacetic acid. M.P.: 159°-161° C.

¹ H NMR (CD₃ COCD₃) ∂ 1.80 (6H, s), 3.17 (3H, s), 6.78-6.84 (3H, m),7.96 (2H, d), 8.06 (2H, d).

Analysis calculated for C₁₉ H₁₆ F₂ O₅ S: C, 57.86; H, 4.09; Found: C,57.66; H, 4.30

EXAMPLE 43-Phenoxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Step 1 3-Phenoxy-5,5-dimethyl-4-(4-(methylthio)phenyl)-5H-furan-2-one

Following the procedure described for example 1, Step 4, the titlecompound was prepared from phenoxyacetic acid and2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (example 1, Step4).

¹ H NMR (CD₃ COCD₃) ∂ 1.79 (6H, s), 2.51 (3H, s), 7.03-7.10 (3H, m),7.30-7.37 (4H, m), 7.72 (2H, d).

Step 23-Phenoxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

The compound obtained in Step 1 (150 mg, 0.46 mmol) was stirred indichloromethane (5 mL) with 3-chloroperoxybenzoic acid (250 mg, 1.38mmol) for 18 hrs. The reaction mixture was diluted with ethyl acetate,washed with saturated sodium bicarbonate, brine, dried over MgSO₄,filtered and the solvent evaporated under vacuum. The residue wastriturated in Et₂ O to afford the title compound. M.P.: 135°-136° C.

¹ H NMR (CD₃ COCD₃) ∂ 1.78 (6H, s), 3.14 (3H, s), 7.05-7.08 (3H, m),7.28-7.30 (2H, m), 7.92 (2H, d), 8.01 (2H, d).

Analysis calculated for C₁₉ H₁₈ O₅ S: C, 63.67; H, 5.06; S, 8.95; Found:C, 64.02; H, 5.10: S, 8.84

EXAMPLE 53-(2,4-Difluorophenoxy)-5,5-dimethl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Step 1 2-Bromoacetic acid,2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester.

To a 0° C. solution of2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one (4.0 g, 16.5mmol, example 1, Step 3) in dichloromethane (100 mL) was added pyridine(23.5 mL, 29 1 mmol) and bromoacetyl bromide (24.9 mL, 285.3 mmol)portionwise over 2 hrs. The reaction mixture was allowed to warm to r.t.and stirred for a further hour. The mixture was diluted withdichloromethane, washed with 1N HCl, brine, filtered through cotton andthe solvent was evaporated under vacuum. Purification by silica gelchromatography (40% EtOAc/Hex.) provided 3.50 g of the title compound.

¹ H NMR (CD₃ COCD₃) ∂ 1.75 (6H, s), 3.20 (3H, s), 4.00 (2H, s), 8.05(2H, m), 8.25 (2H, m).

Step 2 2-(2,4-Difluorophenoxy)acetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one-2-yl ester

Sodium hydride, 60% dispersion (66mg, 1.66 mmol), was rinsed withhexane, suspended in 7 mL of DMF and cooled to 0° C. To this suspensionwas added 2,4-difluorophenol (170 μL, 1.79 mmol). After 5 minutes at 0°C., 2-bromoacetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-oneester (Step 1) (233 mg, 1.79 mmol) was added and the reaction mixturewas stirred for 30 minutes. Dichloromethane was added and the mixturewas washed with 1N HCl and the organic solvent was evaporated undervacuum. The residue was dissolved in 25% EtOAc/Et₂ O and washed with 1NNaOH, water (2×) brine and dried over MgSO₄. After filtration andevaporation of the solvent under vacuum 470 mg of the title compound wasobtained.

¹ H NMR (CD₃ COCD₃) ∂ 1.75 (6H, s), 3.20(3H, s), 4.80 (2H, s), 6.60 (1H,m), 6.75 (1H, m), 7.00 (1H, m), 8.05 (2H, m), 8.20 (2H, m).

Step 33-(2,4-Difluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

To a solution of 2-(2,4-difluorophenoxy)acetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one-2-yl ester (Step 2)(470 mg, 1.14 mmol) in acetonitrile (7 mL) was added DBU (187 μL, 1.25mmol) and the resulting solution was heated at 50° C. for 20 minutes.After cooling to r.t. dichloromethane was added and the mixture waswashed with 1N HCl, brine, filtered over cotton and the solventevaporated under vacuum. Purification by silica gel chromatographyfollowed by a swish in EtOAc/Et₂ O afforded 122 mg of the titlecompound.

¹ H NMR (CD₃ COCD₃) ∂ 1.70 (6H, s), 3.15 (3H, s), 6.90 (1H, m), 7.10(1H, m), 7.30 (1H, m), 7.85 (2H, m), 8.00 (2H, m).

EXAMPLE 63-(4-Chlorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for example 1, the title compound wasprepared from 4-chlorophenoxyacetic acid. M.P.: 113°-114° C.

¹ H NMR (CD₃ COCD₃) ∂ 1.77 (6H, s), 3.15 (3H, s), 7.11 (2H, d), 7.31(2H, d), 7.91 (2H, d), 8.04 (2H, d)

EXAMPLE 73-(3,4-Dichlorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for example 1, the title compound wasprepared from 3,4-dichlorophenoxyacetic acid. M.P.: 144°-145° C.

¹ H NMR (CD₃ COCD₃) ∂ 1.78 (6H, s), 3.15 (3H, s), 7.12-7.15 (1H, m),7.35-7.36 (1H, s), 7.49 (1H, d), 7.92 (2H, d), 8.04 (2H, d).

EXAMPLE 83-(4-Fluorophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for example 1, the title compound wasprepared from 4-fluorophenoxyacetic acid.

¹ H NMR (CD₃ COCD₃) ∂ 1.76 (6H, s), 3.14 (3H, s), 7.02-7.13 (4H, m),7.91 (2H, d), 8.01 (2H, d).

EXAMPLE 93-(4-Fluorophenylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for example 1, the title compound wasprepared from 4-fluorophenylthioacetic acid.

¹ H NMR (CDCl₃) ∂ 1.55 (6H, s), 3.08 (3H, s), 6.85 (2H, m), 7.26 (2H,m), 7.35 (2H, d), 7.94 (2H, d)

EXAMPLE 103-(3,5-Difluorphenylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

To a mixture of 3,5-difluorothiophenol (1.0 g) and methyl bromoacetate(1.2 g) in methanol (20 mL) was added 2 mL of a solution of NaOH (0.69mL of 10N in 3 mL of water), the mixture was stirred for 1 h, then 2 mLof 10N NaOH was added and the mixture stirred for another hour. Thesolvent was evaporated under vacuum, the residue taken in water andwashed with Et₂ O, then acidified with 1N HCl and extracted with ether.The ether extract was washed with water, dried over MgSO₄, filtered andthe solvent evaporated under vacuum giving 850 mg of3,5-difluorophenylthioacetic acid. This acid was reacted as in Step 1 toafford the title compound.

¹ H NMR (CDCl₃) ∂ 1.60 (6H, s), 3.10 (3H, s), 6.60-6.80 (3H, m), 7.45(2H, d), 8.00 (2H, d).

EXAMPLE 113-Phenylthio-5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for example 1, the title compound wasprepared from phenylthioacetic acid. M.P.: 98°-114° C.

¹ H NMR (CD₃ COCD₃) ∂ 1.61 (6H, s), 3.16 (3H, s), 7.21-7.30 (5H, m),7.61 (2H, d), 7.96 (2H, d).

Analysis calculated for C₁₉ H₁₈ O₄ S₂ : C, 60.94; H, 4.84; S, 17.12;Found: C, 61.01; H, 4.90: S, 16.94

EXAMPLE 123-(N-Phenylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Step 1 2-Phenylaminoacetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester

Following the procedure described in example 13 Step 1 but using anilinethe title compound was obtained.

¹ H NMR (CD₃ COCD₃) ∂ 1.70 (6H, s), 3.15 (3H, s), 3.95 (2H, br s), 5.15(1H, br s), 6.40 (2H, m), 6.55 (1H, m), 7.00 (2H, m), 8.00 (2H, m), 8.25(2H, m).

Step 23-N-Phenylamino-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described in example 13 Step 2 but using2-phenylaminoacetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester the titlecompound was obtained.

¹ H NMR (CD₃ COCD₃) ∂ 1.65 (6H, s), 3.05 (3H, s), 6.70 (3H, m), 6.95(2H, m), 7.25 (1H, br s), 7.50 (2H, m), 7.75 (2H, m).

EXAMPLE 133-(N-Methyl-N-phenylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Step 1 2-(N-Phenyl-N-methylamino)acetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester

To a solution of 2-bromoacetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (example 5,Step 1) (1.0 g, 2.75 mmol) in toluene (2.5 mL) was added N-methylaniline(3.0 mL, 27.5 mmol) and the resulting solution was heated at 115° C. for16 hrs. After cooling to r.t. the reaction mixture was washed with brineand filtered through cotton. Purification by silica gel chromatographyprovided 850 mg of the title compound.

Step 23-(N,-Methyl-N-phenylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

To a solution of 2-(N-phenyl-N-methylamino)acetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (700 mg, 1.80mmol) in acetonitrile (3 mL) was added DBU (2.7 mL, 18.0 mmol) and theresulting solution was heated at 60° C. for 1 h. After cooling to r.t.dichloromethane was added and the mixture was washed with 1N HCl, brineand filtered through cotton and the solvent was evaporated under vacuum.Purification by silica gel chromatography followed by swish inEtOAc/Hex. afforded 266 mg of the title compound.

¹ H NMR (CD₃ COCD₃) ∂ 1.70 (6H, s), 3.05 (3H,s), 3.15 (3H, s), 6.70 (1H,m), 6.80 (2H, m), 7.10 (2H, m), 7.65 (2H, m), 7.90 (2H, m)

EXAMPLE 143-Cyclohexyloxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Step 1 2-Bromo-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one

To a solution of 2-methyl-1-(4-(methylthio)phenyl)propan-1-one (example,1, Step 1) (417.94 g) in ethyl acetate (1.2 L) and cyclohexane (1.7 L)was added bromine (110 mL) portionwise. After stirring for 10 min themixture was washed with water, saturated sodium bicarbonate and brine.To this mixture was then added sodium tungstate (6.7 g), Aliquat 336 (25g) and water (200 mL). The mixture was then heated to 50° C. andhydrogen peroxide (30%, 600 mL) was added slowly. Ethyl acetate andwater were then added to the mixture and the organic layer separated,washed with water, dried over sodium sulfate, filtered and the titlecompound crystalized and was collected by filtration.

Step 2 2-Cyclohexyloxyacetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester

A solution of 2-cyclohexyloxyacetic acid (1.74 g, 11 mmol),2-bromo-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one (3.05 g, 10mmol) and diisopropylethylamine (2.20 g, 17 mmol) in 30 mL of ethanolwas refluxed for 15 h. The solvent was evaporated and the residuedissolved in water and extracted with EtOAc, washed with 5% HCl,saturated sodium bicarbonate, brine and dried over MgSO₄, filtered andthe solvent evaporated under vacuum. Purification by silica gelchromatography afforded 3.0 g of the title compound.

Step 33-Cyclohexyloxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

A solution of the ester from the previous step (492 mg, 1.29 mmol) andDBU (1 mL) in 5 mL of acetonitrile was heated at reflux for 15 h. To thecooled solution was added 5% HCl and the mixture was extracted withEtOAc, washed with a saturated solution of ammonium chloride and driedover MgSO₄, filtered and the solvent evaporated under vacuum.Purification by silica gel chromatography afforded the title compound.M.P.: 143°-144° C.

¹ H NMR (CD₃ COCD₃) ∂ 1.20-1.35 (3H, m), 1.40-1.50 (3H, m), 1.66 (6H,s), 1.60-1.70 (2H, m), 1.85-1.95 (2H, m), 3.20 (3H, s), 4.85 (1H, m),8.00-8.10 (4H, m)

Analysis calculated for C₁₉ H₂₄ O₅ S: C, 62.62; H, 6.64; Found: C,62.28; H, 6.57

EXAMPLE 15 3-Phenylthio-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

At 0° C., triethylamine (335 μL) was added to a solution ofthiophenoxyacetic acid (161 mg) and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone (272 mg, WO 9500501, example 9, Step 1) in 5 mL of acetonitrileand the mixture was stirred at 0° C. for 1 h. The reaction mixture wasthen cooled to -20° C. and DBU (265 μL) was added. The mixture wasstirred for 30 min. at -20° C. and was quenched by addition of 1N HCl.The product was extracted with EtOAc, dried over sodium sulfate andpartially purified by silica gel chromatography. The impure product wasrecrystalized from EtOAc/Hexane to afford the title compound as a solid

¹ H NMR (CDCl₃) ∂ 3.10 (3H, s), 5.25 (2H, s), 7.24-7.38 (5H, m), 7.93(2H, d), 8.03 (2H, d).

Analysis calculated for C₁₇ H₁₄ O₄ S₂ : C, 58.94; H, 4.07; Found: C,58.88; H, 4.18

EXAMPLE 163-Benzyl-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Step 1 3-Phenylpropanoic acid2-methyl-1-(4-(methylthio)phenyl)propan-1-on-2-yl ester

To a -30° C. solution of2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (1.05 g, example1, Step 2) in dichloromethane (20 mL) was added 3-phenylpropionylchloride (1.68 g) in dichloromethane (10 mL) followed by pyridine (791mg) and the mixture was allowed to warm up slowly to 25° C. and stirredfor 12 h. Ethyl acetate was added to the mixture and it was washed with1N HCl, brine, dried over magnesium sulfate filtered and the solvent wasevaporated under vacuum. Purification by silica gel chromatographyafforded 1.36 g of the title compound.

¹ H NMR (CD₃ COCD₃) ∂ 1.65 (6H, s), 2.50 (3H, s), 2.55-2.65 (2H, t),2.75-2.85(2H, t), 7.10-7.40 (7H, m), 7.90-8.00 (2H, d)

Step 2 3-Benzyl-5,5-dimethyl-4-(4-(methylthio)phenyl)-5H-furan-2-one

To a 0° C. solution of the ester from the previous step (1.14 g) in DMF(10 mL) and THF (2 mL) was added sodium hydride (120 mg of 80%dispersion) and the mixture was stirred for 2 h at 25° C. Then it waspoured over icy 1N HCl and extracted with ethyl acetate, the organiclayer was washed with water, brine, dried over MgSO₄ and the solventevaporated under vacuum. The residue was purified by silica gelchromatography affording 596 mg of the title compound.

¹ H NMR (CD₃ COCD₃) ∂ 1.50 (6H, s), 2.55 (3H, s), 3.50 (2H, s),7.05-7.30 (7H, m), 7.35-7.40 (2H, d)

Step 3 3-Benzyl-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

To a 0° C. solution of the lactone from the previous step (596 mg) indichloromethane (10 mL) and methanol (5 mL) was added portionwise MMPP(2×590 mg) and the mixture was allowed to slowly warm-up to 25° C. After2 h. at 25° C. the mixture was partitioned between dichloromethane andwater, the organic layer was washed with brine, dried over MgSO₄,filtered and the solvent evaporated under vacuum. The residue wasswished in ether to yield 530 mg of the title compound.

Analysis calculated for C₂₀ H₂₀ O₄ S: C, 67.40; H, 5.65; Found: C,67.28; H, 5.78

EXAMPLE 173-(3,4-Difluorophenylhydroxymethyl)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Using a procedure similar to the Steps 1, 2 and 3 of example 19 butusing 3,4-difluorobenzaldehyde as an electrophile the title compound wasobtained.

¹ H NMR (CD₃ COCD₃) ∂ 1.45 (6H, s), 3.15 (3H, s), 5.00 (1H, bs), 5.50(1H, bs), 6.45-6.55 (2H, d), 7.00-7.30 (3H, m), 7.95-8.05 (2H, d).

EXAMPLE 183-(3,4-Difluorobenzoyl)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Using a procedure similar to Step 4 of example 19 and using the compoundobtained in example 17, the title compound was obtained

¹ H NMR (CD₃ COCD₃) ∂ 1.75 (6H, s), 3.10 (3H, s), 7.35-7.45 (1H, m),7.65-7.75 (2H, d), 7.75-7.90 (2H, m), 7.95-8.05 (2H, d).

EXAMPLE 193-Benzoyl-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Step 1 Acetic acid 2-methyl-1-(4-methylthiophenyl)propan-1-on-2-yl ester

To a 0° C. solution of2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (150 g, example1, Step 2), DBU (217 g) and DMAP (7 g) in dichloromethane (850 mL) wasadded acetyl chloride (112.2 g) dropwise and the mixture was stirred for6 h. at 25° C. More DBU (32.5 g) was added and the mixture was stirredan additionnal 16 h. The reaction mixture was poured over 2N HCl (800mL) and the organic layer was separated, washed with a saturatedsolution of NaHCO₃, dried over MgSO₄, filtered and the solvent wasevaporated under vacuum. The residue was swished in Et₂ O, then 25%ethyl acetate in hexane, then filtered and dried giving 74 g of thetitle compound.

¹ H NMR (CD₃ COCD₃) ∂ 1.60 (6H, s), 1.90 (3H, s), 2.55 (3H, s), 7.30(2H, d), 8.00 (2H, d).

Step 2 5,5-Dimethyl-4-(4-(methylthio)phenyl)-5H-furan-2-one

To a 0°-5° C. solution of the ester from the previous step (74 g) in DMF(1.2 L) was added NaH (9 g, 80% dispersion) portionwise and the mixturewas stirred for 3 h. Saturated aquous NH₄ Cl was added slowly. Themixture was then partitioned between ethyl acetate and water, theorganic layer was washed with water, dried with Na₂ SO₄, filtered andthe solvent was evaporated under vacuum. The residue was swished in 30%ethyl acetate/hexane to yield the title compound (38 g).

¹ H NMR (CD₃ COCD₃) ∂ 1.70 (6H, s), 2.55 (3H, s), 6.40 (1H, s), 7.40(2H, d), 7.70 (2H, d).

Step 35,5-Dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(phenylhydroxymethyl)-5H-furan-2-one

To a -78° C. solution of the lactone (702 mg) obtained in the previousstep in THF was added 0.67M LDA (9.25 mL) and the mixture was reactedfor 5 min. Benzoyl chloride (913 mg) was then added at -78° C. and after15 min the mixture was poured over icy 1N HCl. The organic material wasextracted with ethyl acetate, washed with brine, dried with MgSO₄,filtered and the solvent was evaporated under vacuum. The residue wasdissolved in dichloromethane (10 mL) and methanol (10 mL) and thesolution cooled to 0° C. MMPP (4.9 g) was added and the mixture warmedand stirred at 25° C. for 2 h. The mixture was poured over icy water andthe organic layer was dried over MgSO₄, filtered and the solventevaporated under vacuum. The residue was purified by silica gelchromatography to yield 190 mg of compound which was dissolved inmethanol (2 mL) and THF (1 mL), cooled to 0° C. and a catalytic amountof NaOH was added. The mixture was poured in icy water and extractedwith ethyl acetate, the organic layer was washed with brine, dried overMgSO₄, filtered and the solvent evaporated under vacuum.

Step 43-Benzoyl-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

The residue was dissolved in acetone (3 mL), and Jone's reagent (3M, 150μL) was added. The mixture was stirred for 1 h. then poured over icywater and extracted with ethyl acetate, the organic layer was washedwith brine, dried over MgSO₄, filtered and the solvent was evaporatedunder vacuum. The residue was swished in ether to yield the titlecompound (123 mg).

Analysis calculated for C₂₀ H₁₈ O₅ S: C, 64.85; H, 4.84; Found: C,64.63; H, 5.23

EXAMPLE 20 4-(4-(Methylsulfonyl)phenyl)-3-phenoxy-1-oxaspiro4.4!non-3-en-2-one

Using a procedure similar to the one used in example 1 but using(1-hydroxycyclopentyl)-(4-(methylsulfonyl)phenyl)methanone from example21, Step 3 and phenoxyacetic acid the title compound was obtained.

¹ H NMR (CDCl₃) ∂ 1.80-2.30 (8H, m), 3.04 (3H, s), 6.95-7.35 (5H, m),7.75 (2H, d), 7.95 (2H, d).

EXAMPLE 21 4-(4-(Methylsulfonyl)phenyl)-3-phenylthio-1-oxaspiro4.4!non-3-en-2-one

Step 1: Cyclopentyl-(4-(methylthio)phenyl)methanone

To a suspension of anhydrous aluminum chloride (9.3 g, 69.6 mmol) in 58mL CHCl₃ at 0° C. was added dropwise cyclopentanecarbonyl chloride (10.0g, 75.4 mmol), followed by thioanisole (7.21 g, 58.0 mmol). The ice bathwas removed and the mixture was stirred at room temperature for 2 h.Water (200 ml) was added with cooling, the layers were separated and theaqueous layer was extracted with CHCl₃ (3×50 mL). The combined aqueouslayers were dried over MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel (4% EtOAc/hexane) to give 11.9 g of thetitle ketone (93%).

¹ H NMR (CD₃ COCD₃) ∂ 7.94 (d, 2H), 7.36 (d, 2H), 3.79 (q, 1H), 2.56 (s,3H), 2.00-1.71 (m, 4H), 1.70-1.50 (m, 4H).

Step 2: (1-Hydroxycyclopentyl)-(4-(methylthio)phenyl)methanone

To a solution of the ketone from Step 1 (7.2 g, 32.7 mmol) in 4.7 mlCCl₄ and 9.6 ml toluene was added Aliquat 336 (2.11 g, 5.20 mmol) andpowdered NaOH (2.88 g, 71.9 mmol) and the mixture was stirred for 16 hat r.t. To the brown mixture was added 100 ml of 5% aq. HCl andextracted with EtOAc (4×100 ml). The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated. Chromatographyon silica gel (20% EtOAc/hexane) gave 5.4 g of the title compound as awhite waxy solid (70%).

¹ H NMR (CD₃ COCD₃) ∂ 8.11 (d, 2H), 7.31 (d, 2H), 4.63 (s, 1H,disappears by D₂ O wash), 2.56 (s, 3H), 2.24 (m, 2H), 1.89 (m, 4H), 1.71(m, 2H).

Step 3 (1-Hydroxycyclopentyl)-(4-(methylsulfonyl)phenyl)methanone

The sulfide obtained in Step 2 (56 g) was dissolved in dichloromethane(800 mL) and methanol (200 mL) and treated with MMPP (139 g) and stirredfor 3 h. The organic layer was diluted with dichloromethane, washed withwater and brine, dried over MgSO₄, filtered and the solvent evaporatedto afford the title compound.

Step 4 4-(4-(Methylsulfonyl)phenyl)-3-phenylthio-1-oxaspiro4.4!non-3-en-2-one

The hydroxyketone from the previous step was reacted withphenylthioacetic acid as in the procedure for example 1, Step 4 toafford the title compound.

¹ H NMR (CDCl₃) ∂ 1.70-2.05 (8H, m), 3.06 (3H, s), 7.10-7.25 (5H, m),7.35 (2H, d), 7.90 (2H, d).

EXAMPLE 22 4-(2-Oxo-3-phenylthio-1-oxa-spiro4,4!non-3-en-4-yl)benzenesulfonamide

To a solution of 1-(hydroxycyclopentyl)-(4-methylthiophenyl)methanone(52 g, example 21, Step 2) in CH₂ Cl₂ (400 mL) and methanol (200 mL) at0° C. was added portionwise MMPP (61 g). After stirring for 3 h thereaction mixture was washed with water, dried over Na₂ SO₄, filtered andevaporated to dryness to provide the sulfoxide intermediate which (7.56g) was dissolved in TFAA (100.0 mL) and refluxed for 3 h. The mixturewas cooled to 0° C. and 10N NaOH (24 mL), was added dropwise and undernitrogen. After vigorous stirring for 0.5 h, acetic acid (100 mL) andwater (20 mL) was added. The mixture was cooled to 0° C. and chlorinegas was bubbled for 20 min. The excess chlorine was removed under vacuumand the mixture was poured over icy water and extracted with ethylacetate. The extracts were washed with water, saturated NaHCO₃ andbrine. The organic layer was cooled to 0° C. and t-butylamine (10 mL)was added and stirred for 1 h. The reaction mixture was diluted withwater and neutralized with 6N HCl, washed with brine, dried over MgSO₄filtered and the solvent evaporated under vacuum. The residue wasswished in ether. This hydroxyketone (325 mg) was then reacted as inexample 1, Step 4 using phenylthioacetic acid (200 mg) to give anintermediate (300 mg) which was stirred in dichloromethane (2 mL) andtrifluoroacetic acid (8 mL) for 18 h. The solvents were then evaporatedunder vacuum and the residue was recrystallized from ethanol to affordthe title compound.

¹ H NMR (CD₃ COCD₃) ∂ 1.65-2.20 (8H, m), 6.68 (2H, br s), 7.25 (5H, m),7.55 (2H, d), 7.95 (2H, d).

EXAMPLE 233-(4-Fluorobenzyl)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Using a procedure similar to the one for example 16 but using3-(4-fluorophenyl)propionyl chloride the title compound was obtained.

¹ H NMR (CD₃ COCD₃) ∂ 1.50 (6H, s), 3.15 (3H, s), 4.45 (2H, s),7.05-7.15 (2H, m), 7.50-7.60 (2H, d), 7.85-7.95 (2H, m), 7.95-8.05 (2H,d).

EXAMPLE 243-(3,4-Difluorophenoxy)-5-methoxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Step 1 2-Bromo-1-(4-(methylsulfonyl)phenyl)propan-1-one

Following a procedure similar to the one used in example 1, Step 1 butusing propionyl chloride, 1-(4-(methylsulfonyl)phenyl)propan-1-one wasobtained. A solution of this compound (163.4 g) in chloroform (2.2 L)was then cooled to 0° C. and treated with bromine (40 mL in 200 mLCHCl₃) and concentrated HBr (10 mL). The reaction mixture was washedwith water, saturatd sodium bicarbonate and brine, dried over sodiumsulfate, filtered and the solvent evaporated under vacuum. The residuewas swished in ethyl acetate:hexane 1:1 to give the title compound (191g).

Step 25-Hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-phenylthio-5H-furan-2-one

To a mixture of 2-bromo-1-(4-(methylsulfonyl)phenyl)propan-1-one (6.0 g,20.6 mmol) and thiophenoxyacetic acid (3.8 g, 22.6 mmol) in acetonitrile(60 mL) was added triethylamine (4.0 mL, 28.8 mmol). The mixture wasstirred at r.t. for 3 h. T.L.C. showed no bromoketone remaining and DBU(4.0 mL) was added. The mixture was stirred at r.t. for 1 h., then airwas bubbled through the mixture for another hour. After dilution withwater, the mixture was extracted with EtOAc. The EtOAc extract waswashed with 1N aquous HCl, brine, dried over MgSO₄, filtered and thesolvent evaporated under vacuum. The residue was swished in Et₂ O togive the title compound (6.0 g) as a pale yellow powder.

¹ H NMR (CD₃ COCD₃) ∂ 1.68 (3H, s), 3.16 (3H, s), 6.86 (1H, s), 7.35(5H, m), 7.78 (2H, d), 7.98 (2H, d).

Step 35-Methoxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-phenylthio-5H-furan-2-one

The alcohol (2.58, 6.6 mmol) from the previous step was dissolved inmethanol (100 mL), THF (20 mL) and concentrated HCl (5 mL) and heated at70° C. for 24 h. After cooling to 0° C. the precipitate formed wasfiltered, washed with methanol and dried under vacuum to give the titlecompound (2.0 g) as a yellow solid.

¹ H NMR (CD₃ COCD₃) ∂ 1.65 (3H, s), 3.15 (3H, s), 3.40 (3H, s),7.18-7.40 (5H, m), 7.88 (2H, d), 7.98 (2H, d).

Step 43-(3,4-Difluorophenoxy)-5-methoxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

To a solution of the compound obtained in the previous step (2.0 g, 5.1mmol) in dichloromethane (100 mL) at r.t. was added mCPBA (4.0 g,Aldrich 57-86%, ˜16 mmol). The mixture was stirred at r.t. for 3 h andmore mCPBA (2.0 g) was added. After stirring for another hour themixture was washed with 1N NaOH, brine, dried and concentrated undervacuum to yield a disulfone as a white foam (2.0 g). To a solution of3,4-difluorophenol (2.0 g, 14.9 mmol) in DMF was added 10N NaOH (1 mL,10 mmol). After 30 min. a solution of the above disulfone (2.0 g, 4.7mmol) in DMF was added. The mixture was heated at 80°-85° C. for 1.5 h.After cooling the mixture was diluted with water, extracted with EtOAc,the organic extracts were washed with 1N NaOH, 1N HCl, brine, dried overMgSO₄, filtered and the solvent evaporated under vacuum. Purification bysilica gel chromatography afforded the title compound as a white solid(600 mg).

¹ H NMR (CD₃ COCD₃) ∂ 1.86 (3H, s), 3.16 (3H, s), 3.40 (3H, s),6.95-7.40 (3H, m), 8.08 (2H, d), 8.16 (2H, d).

EXAMPLE 253-(5-Chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

To a mixture of 2-chloroacetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (1.0 g, 3.13mmol, prepared similarly to the compound of example 5, Step 1) and5-chloro-2-pyridinol (0.41 g, 3.16 mmol) in CH₃ CN (20 mL) was added DBU(1.5 mL, 10.0 mmol) at r.t. The mixture was stirred for 1 h, then heatedat 65°-70° C. for 3 h. The volatile solvents were removed in vacuo. Theresidue was chromatographed over silica gel and eluted with hexane:EtOAc(1:1) to yield a colorless oily residue which was swished in Et₂ O toprovide the title compound as a white powder (230 mg).

¹ H NMR (CD₃ COCD₃) ∂ 1.80 (6H, s), 3.20 (3H, s), 7.18 (1H, d), 7.94(3H, m), 8.06 (2H, d), 8.19 (1H, d).

EXAMPLE 263-(2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for example 25, the title compound wasprepared from 2-hydroxypyridine.

¹ H NMR (CD₃ COCD₃) ∂ 1.78 (6H, s), 3.15 (3H, s), 7.00-7.20 (2H, m),7.80-8.20 (6H, m).

EXAMPLE 273-(6-Methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for example 25, the title compound wasprepared from 2-hydroxy-6-methylpyridine.

¹ H NMR (CD₃ COCD₃) ∂ 1.75 (6H, s), 3.14 (3H, s), 6.85 (1H, d), 7.00(1H, d), 7.70 (1H, t), 7.90 (2H, d), 8.00 (2H, d).

EXAMPLE 283-(3-Isoquinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for example 25, the title compound wasprepared from 3-hydroxyisoquinoline.

¹ H NMR (CD₃ COCD₃) ∂ 1.80 (6H, s), 3.14 (3H, s), 7.40-8.10 (9H, m),9.00 (1H, s).

EXAMPLE 29 3-(4-(Methylsulfonyl)phenyl)-2-phenoxycyclopent-2-enone

Step 1 1-(4-(Methylthio)phenyl)-5-phenoxypenta-1,4-dione

To a mixture containing 1-phenoxybut-3-en-2-one (1.0 g) (A. G. Schultz,R. D. Lucci, W. Y. Fu, M. H. Berger, J. Erhardt and W. K. Hagmann, J.Amer. Chem. Soc. 100, 2150, (1978)), 4-(methylthio)benzaldehyde (0.62 g)and triethylamine (0.343 mL) in 1,4-dioxane (20 mL) was added3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (110 mg). Afterstirring 4 h. at 100° C. the reaction mixture was extracted with EtOAc,dried over MgSO₄, filtered and the solvent evaporated under vacuum. Theresidue was purified by silica gel chromatography (20% EtOAc/Hexane) toafford 140 mg of the title compound as an oil.

Step 2 3-(4-(Methylthio)phenyl)-2-phenoxycyclopent-2-enone

To the diketone of Step 1 (120 mg) in methanol (80 mL) was added DBU(0.1 mL). The resulting mixture was heated at 60° C. for 18 h. Themethanol was then evaporated and to the crude mixture was addedsaturated aqueous ammonium chloride, the mixture was then extracted withEtOAc, the organic layer was dried over MgSO₄, filtered, and the solventevaporated under vacuum. The residue was purified by silica gelchromatography (20% EtOAc/hexane) to afford the title compound.

Step 3 (4-(Methylsulfonyl)phenyl)-2-phenoxycyclopent-2-enone

To the compound obtained in Step 2 (60 mg) in dichloromethane (4.5 mL)and methanol (2.4 mL) was added Oxone® (450 mg) in water (1 mL) and thereaction mixture was stirred for 1 h. Water was added to the mixturewhich was then extracted with dichloromethane, the organic layers werecombined and dried over MgSO₄, filtered and the solvent evaporated undervacuum. Purification by silica gel chromatography afforded the titlecompound.

¹ H NMR (CD₃ COCD₃) ∂ 2.65 (2H, t), 3.15 (3H, s), 3.20 (2H, t),7.05-7.35 (5H, m), 8.10 (4H, m).

EXAMPLE 302-(3,4-difluorophenoxy)-3-(4-methylsulfonylphenyl)-cyclopent-2-enone

Step 1: 3,4-Difluorophenoxymethyl vinyl ketone

To a suspension of 3,4-difluorophenoxy acetic acid (5.00 g, 25.7 mmol)lithium salt in DME (20 mL) was added to a 1M THF solution of vinylmagnesium bromide (38 mmol). After a period of 18 h, the resulting clearsolution was poured over 1N HCl (67 mL). The aqueous phase was thenextracted with Et₂ O. The ethereal phase was washed with H₂ O, 1M K₂ CO₃then H₂ O. After drying over MgSO₄ and evaporation an orange oil wasobtained and used as such for the next step.

Step 2:2-(3,4-difluorophenoxy)-3-(4-methylsulfonylphenyl)cyclopent-2-enone

Following the procedure described in Example 29 but using the compoundobtained in the previous step the title compound was obtained.

¹ H NMR (CD₃ COCD₃) ∂ 2.60 (2H, t), 3.15 (3H, s), 3.20 (2H, t), 6.90(1H, m), 7.15 (1H, m), 7.25 (1H, Q), 8.10 (4H, 2d).

EXAMPLE 323-(5-Benzothiophenyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 5-hydroxybenzothiophene.

M.P.: 150°-152° C. ¹ H NMR (CD₃ COCD₃) ∂ 1.78 (6H, s), 3.08 (3H, s),7.17 (1H, dd), 7.32 (1H, d), 7.56 (1H, d), 7.68 (1H, d), 7.92-7.99 (5H,m).

EXAMPLE 375,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(pyridin-4-yloxy)-5H-furan-2-one

To a R.T. solution of 2-chloroacetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (318 mg, 1 mmol)in DMF (5 mL) was added 4-pyridone (380 mg, 4.0 mmol) followed by DBU(623 mg, 4.1 mmol) and the mixture was slowly warmed up to R.T. for 16hrs and then to 60°-70° C. for 1-2 hours. The mixture was cooled to R.T.and poured on icy dilute NH₄ Cl and EtOAc; the organic layer wasseparated and the aqueous further extracted with EtOAc. The combinedorganic layers were washed with brine, dried with Na₂ SO₄ and thesolvents were removed in vacuo. The residue was purified on silica gelchromatography (1/1, Acetone/toluene) to provide the title compound.

¹ H NMR (CD₃ COCD₃) δ 1.8(6H,s), 3.15(3H,s), 7.05-7.15(2H,m), 7.9-8.1(4H,AB), 8.4-8.5(2H,m).

EXAMPLE 385,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(pyridin-3-yloxy)-5H-furan-2-one

To a R.T. solution of 2-chloroacetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (318 mg, 1 mmol)in DMF (5 mL) was added 3-hydroxypyridine (95 mg, 1 mmol) followed byDBU (623 mg, 4.1 mmol) and the mixture was slowly warmed up to R.T. for16 hrs and then to 60°-70° C. for 1-2 hours. The mixture was cooled toR.T. and poured on icy dilute NH₄ Cl and EtOAc; the organic layer wasseparated and the aqueous further extracted with EtOAc. The combinedorganic layers were washed with brine, dried with Na₂ SO₄ and thesolvents were removed in vacuo. The residue was purified on silica gelchromatography (1/1, Acetone/toluene) to provide the title compound.

Analysis calculated for C₁₈ H₁₇ NO₅ S: C, 60.16; H, 4.77; N, 3.90.Found: C, 60.01; H, 4.81; N, 3.90.

EXAMPLE 393-(2-Methyl-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared using 5-hydroxy-2-methyl pyridine M.P.: 168°-169° C.

¹ H NMR (CD₃ COCD₃) δ 1.77 (6H, s), 2.41 (3H, s), 3.15 (3H, s), 7.14(1H, d), 7.37 (1H, dd), 7.93 (2H, d), 8.03 (2H, d), 8.25 (1H, d).

EXAMPLE 443(2-Fluoro-4-trifluoromethyl)phenoxy-4-(4-methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one

Following the procedure for Example 25, the title compound was preparedfrom 2-fluoro-4-trifluoromethylphenol; m.p.: 192-194.

¹ H NMR (CD₃ COCD₃) d 1.78 (6H, s), 3.16 (3H, s), 7.49 (2H, m), 7.64(1H, d, J=11.6 Hz), 7.95 (2H, d, J=8.3 Hz), 8.05 (2H, d, J=8.5 Hz).

Analysis calculated for C₂₀ H₁₆ F₄ O₅ S: C, 54.06; H, 3.63; Found: C,54.09, H, 3.72.

EXAMPLE 453-(5-Chloro-2-pyridylthio)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 5-chloro-2-mercaptopyridine.

¹ H NMR(CD₃ COCD₃) δ 1.70(6H, s), 3.20(3H, s), 7.38(1H, d), 7.72(3H, m),8.06(2H, d), 8.42(1H, m).

EXAMPLE 462-(3,5-Difluorophenoxy)-3-(4-methylsulfonylphenyl)-cyclopent-2-enone

Using similar protocol described for Example 29 but using1-(3,5-difluorophenoxy)but-3-en-2-one the title compound was obtained.

¹ H NMR (CD₃ COCD₃) δ 2.60 (2H, t), 3.15 (3H, s), 3.20 (2H, t), 6.60 to6.85 (3H, m), 8.10 (4H, 2d).

EXAMPLE 473-(2-Pyrimidinoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 2-hydroxypyrimidine hydrochloride.

¹ H NMR(CD₃ COCD₃) δ 1.78(6H, s), 3.18(3H, s), 7.34(1H, t), 7.40(2H, d),8.06(2H, d), 8.68(2H, d).

EXAMPLE 483-(3-Methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Step 1: 2-Hydroxy-3-methylpyridine

To 10% aqueous H₂ SO₄ (90 mL) at 0° C. was added2-amino-3-methylpyridine (6.0 g, 56 mmol). The mixture was stirred at 0°C. for 30 mins and a solution of 4N aqueous NaNO₂ (13 mL) was addeddropwise over a period of 15 min. The mixture was further stirred andwarmed to rt over 1 h. The pH was then adjusted to 6-7 by the additionof 10N aqueous NaOH. The whole mixture was then extracted with CHCl₃,washed with H₂ O, dried (anhydrous MgSO₄) and concentrated in vacuo. Thecrude material was swished with Et₂ O to give the title compound (2.5 g,42%) as a white solid.

¹ H NMR(CD₃ COCD₃) δ 2.02(3H, s), 6.10(1H, m), 7.30(2H, m).

Step 2:3-(3-Methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 2-hydroxy-3-methylpyridine.

¹ H NMR(CD₃ COCD₃) δ 1.78(6H, s), 2.30(3H, s), 3.14(3H, s), 7.05(1H, m),7.65(1H, m), 7.95(3H, m), 8.02(2H, d).

EXAMPLE 493-(3-Chloro-5-pyridiloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furano2-one

Following the procedure described for Example 25, the title compound wasprepared using 2-chloro-5-hydroxypyridine. M.P.: 176°-177° C.

¹ H NMR (CD₃ COCD₃) δ 1.79 (6H, s), 3.16 (3H, s), 7.70 (1H, m), 7.96(2H, d), 8.05 (2H, d), 8.33 (1H, d), 8.40 (1H, d).

EXAMPLE 513-(3-(1,2,5-Thiadiazolyl)oxy)-4-(4-(methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one

Following the procedure for example 25, the title compound was preparedfrom 3-hydroxy-1,2,5-thiadiazol; m.p.: 127-129.

¹ H NMR (CD₃ COCD₃) δ 1.78 (6H, s), 3.16 (3H, s), 7.92 (2H, d, J=8.6Hz), 8.06 (2H, d, J=8.6 Hz), 8.49 (1H, s).

Analysis calculated for C₁₅ H₁₄ N₂ O₅ S₂ : C, 49.17; H, 3.85; N, 7.65;Found: C, 49.01, H, 3.84; N, 7.37.

EXAMPLE 523-(5-Isoquinolinoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 5-hydroxyisoquinoline.

¹ H NMR(CD₃ COCD₃) d 1.80(6H, s), 3.10(3H, s), 7.38(1H, d), 7.55(1H, t),7.85(1H, d), 7.95(4H, m), 8.04(1H, d), 8.58(1H, d), 9.30(1H, s).

EXAMPLE 533-(6-Amino-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 2-hydroxy-6-aminopyridine.

M.P.: 165°-166° C. ¹ H NMR (CD₃ COCD₃) δ 1.74 (6H, s), 3.14 (3H, s),5.52 (2H, s, br), 6.17 (1H, d), 6.24 (1H, d), 7.41 (1H, t), 7.90 (2H,d), 8.02 (2H, d).

EXAMPLE 543-(3-Chloro-4-fluoro)phenoxy-4-(methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one

Following the procedure for Example 25, the title compound was preparedfrom 3-chloro-4-fluorophenol; m.p.: 130°-132° C.

¹ H NMR (CD₃ COCD₃) δ 1.76 (6H, s), 3.14 (3H, s), 7.10 (1H, m), 7.24(1H, t, J=9Hz), 7.30 (1H, m), 7.92 (2H, d, J=8.5 Hz), 8.03 (2H, d, J=8.5Hz).

EXAMPLE 553-(6-Quinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared using 6-hydroxyquinoline. M.P.: 171°-172° C.

¹ H NMR (CD₃ COCD₃) δ 1.82 (6H, s), 3.08 (3H, s), 7.46 (1H, m),7.53-7.60 (3H, m), 7.95-8.01 (5H, m), 8.23 (1H, m), 8.80 (1H, m).

EXAMPLE 563-(5-Nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 2-hydroxy-5-nitropyridine.

¹ H NMR(CD₃ COCD₃) δ 1.80(6H, s), 3.18(3H, s), 7.38(1H, d), 7.92(2H, d),8.05(2H, d), 8.66(1H, m), 9.05(1H, m).

EXAMPLE 573-(2-Thiazolylthio)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared using 2-mercaptothiazole. M.P.: 174°-176° C.

¹ H NMR (CD₃ COCD₃) δ 1.67 (6H, s), 3.19 (3H, s), 7.59 (1H, d), 7.68(1H, d), 7.74 (2H, d), 8.07 (2H, d).

EXAMPLE 583-(3-Fluoro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared using 5-fluoro-2-hydroxypyridine M.P.: 157°-159° C.

¹ H NMR (CD₃ COCD₃) δ 1.76 (6H, s), 3.16 (3H, s), 7.16 (1H, m), 7.74(1H, m), 7.92 (2H, d), 8.03 (2H, d), 8.07 (1H, m).

EXAMPLE 109a5,5-Dimethyl-4-(4-methylsulfonylphenyl)-3-(2-propoxy)-5H-furan-2-one

Step 1 5,5-Dimethyl-3-hydroxy-4-(4-methylsulfonylphenyl)-5H-furan-2-one

To a 0° C. solution of the alcohol of Example 1, Step 3 (29.5 g, 122mmol) in CH₃ CN (350 mL) were added pyridine (25 mL) and acetoxyacetylchloride (25 g, 183 mmol). After a period of 7 h at r.t., DBU (31 mL)was added to the reaction mixture. After a period of 1 h at 80° C., asecond portion of DBU (35 mL) was added. The reaction mixture was keptat 80° C. for 18 h. The reaction mixture was allowed to cool to r.t. Themixture was poured onto ice-water (2.5 L) containing 100 mL ofconcentrated HCl. The brown solid was collected and dissolved in hotacetonitrile and was filtered through a plug of silica. The solvent wasevaporated and the resultant solid was swished in EtOAc to give thetitle compound (21.2 g, 62%).

Step 25,5-Dimethyl-4-(4-methylsulfonyl)phenyl)-3-(-2-propoxy)-5H-furan-2-one

To a suspension of the alcohol of Step 1 (18.16 g, 64.4 mmol) in benzene(350 mL) were added an excess of 2-iodopropane (19.3 mL) and Ag₂ CO₃(53.3 g, 1.06 mmol). After stirring for 18 h, the reaction mixture wasfiltered and the filtrate was washed with hot EtOAc. After evaporation,the crude compound was purified by flash chromatography (35% to 40%EtOAc/hexane, followed by addition of 5% CH₂ Cl₂) to provide 19 g of thetitle compound.

¹ H NMR (CD₃ COCD₃) δ 1.25 (6H, d), 1.70 (6H, s), 3.20(3H,s),5.20(1H,septet), 8.05 (4H, s).

EXAMPLE 109b5,5-Dimethyl-4-(4-methylsulfonylphenyl)-3-(2-propoxy)-5H-furan-2-one

Step 1: 5,5-Dimethyl-3-hydroxy-4-(4-methylsulfonylphenyl)-5H-furan-2-one

To a 0° C. solution of the alcohol of Example 1, Step 3 (14.0 g, 57.8mmol) in CH₃ CN (180 mL) were added pyridine (10.0 mL) and acetoxyacetylchloride (12.7 g, 93.0 mmol) after a period of 7 h at r.t., DBU (15.0mL) was added to the reaction mixture. After a period of 1 h at 80° C.,a second portion of DBU (20.0 mL) was added. The reaction mixture waskept at 80° C. for 18 h. The reaction mixture allowed to cool to r.t.The mixture was diluted with EtOAc (500 mL) and H₂ O (500 mL) andacidified with 6NHCl. After the addition of brine (100 mL), the aqueousphase was extracted 2 times with EtOAc. The organic phase was evaporatedto provide a brown residue. To the solid was added a 2:1 mixture of CH₂Cl₂ -toluene (150 mL). The solid was filtered and washed with CH₂ Cl₂-toluene to provide 7.0 g of the title compound.

Step 25,5-Dimethyl-4-(4-methylsulfonyl)phenyl)-3-(-2-propoxy)-5H-furan-2-one

To a suspension of the alcohol of Step 1 (100 mg, 0.354 mmol) in benzene(5.0 mL) were added an excess of 2-iodopropane (105 mL) and Ag₂ CO₃ (294mg, 1.06 mmol). After a period of 18 h at 45° C., the reaction mixturewas filtered over celite and washed with CH₂ CL₂. After evaporation, thecrude compound was purified by flash chromatography (35% to 40% EtOAc)to provide 70 mg of the title compound.

¹ H NMR (CD₃ COCD₃) δ 1.25 (6H, d), 1.70 (6H, s), 3.20 (3H, s), 5.20(1H, Septet), 8.05 (4H, s).

Alternatively compound 109 may be prepared in the following manner:

Step A 1: 2-Methyl-1-(4-(thiomethyl)phenyl)propan-1-one

A 500 mL flask was charged under N₂ with 34.5 g (259 mMol) of AlCl₃ and100 mL of ODCB. The vigorously stirred slurry was cooled to 8° C. andisobutyryl chloride (28.6 mL, 261 mMol) was added over 30 min., keepingthe temperature at 10°-15° C.

The addition of isobutyryl chloride was slightly exothermic.

The AlCl₃ /isobutyryl chloride complex was aged at 7° C. for 30 min.Efficient cooling was applied and thioanisole (31.2 g) was added to thereaction mixture over 120 min., maintaining an internal temperature of8°-13° C.

The addition of thioanisole was very exothermic. After the addition ofabout half of thioanisole a heavy yellow precipitate formed. Theprecipitation was accompanied by an exotherm. Gaseous HCl is formed inthe reaction, so that the effluent gas stream should be scrubbed withaqueous NaOH before release into the atmosphere.

The reaction was warmed to 16° C. over 1 h.

The reaction mixture was a thick yellow slurry at this point. HPLCanalysis of a quenched (EtOAc/H₂ O) aliquot indicated completion ofreaction.

The reaction mixture was cooled to 10° C. and 160 mL of 5% aqueous HClwere added over 45 min.

The addition was extremely exothermic and especially the initialaddition required careful temperature monitoring.

The biphasic mixture was vigorously stirred for 60 min. The lowerorganic phase was removed.

A quantitative assay of the organic phase indicated a 98% yield.

Step A 2: 2-Bromo-2-methyl-1-(4-(thiomethyl)phenyl)propan1-one

A 500 mL flask was charged with the solution of the compound from step A1 (246 mMol). Approximately 10% of the bromine (1.3 mL, 26 mMol) wereadded and the reaction mixture was stirred until the red color haddissipated after 45 min. The remainder of the Br₂ (12 mL) was added over60 min.

The reaction was exothermic and the temperature rose to ca. 32° C.

Gaseous HBr was released from the reaction, thus the effluent gas streamwas scrubbed with aqueous NaOH before release into the atmosphere.

The reaction mixture was aged for 2 h at 30° C. when HPLC analysisindicated completion of the reaction

Addition of a slight excess of Br₂ leads to the partial oxidation of thesulfide to the sulfoxide.

The reaction was quenched by the addition of 160 mL H₂ O and theresulting 182.0 mL of organic phase were used directly for the oxidation(next step) (95% assay yield).

Step A 3: 2-Bromo-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one

To a solution of the compound from the previous step in ODCB in a 500 mLreaction vessel with heating jacket, reflux condenser and bottom valvewas added under N₂ a solution of Na₂ WO₄ (0.45 g, 1.4 mMol) and Aliquat336 (2.2 g, 5.4 mMol) in 3.0 mL H₂ O. The heterogeneous reaction mixturewas heated with vigorous stirring to 35° C. and ca. 3.0 mL of H₂ O₂(30%) were added.

The oxidation was extremely exothermic. After an induction period of ca.3 min. the temperature rose quickly to 50°-65° C.

The remainder of the H₂ O₂ (36 mL) was added over 1 h. At the end of theaddition HPLC analysis indicated completion of the reaction.

The reaction mixture was heated to 80° C., the lower organic phase wasremoved and cooled to 6° C. over 1 h.

The product precipitated at ca. 50° C. without seeding.

The slurry was filtered and washed with 25.0 mL of ODCB and 30.0 mL ofhexane and three times with 20.0 mL of 60° C. H₂ O. After drying 37.8 gof the title compound (97% yield, ca. 91% overall yield fromthioanisole) were obtained as a white powder.

Step A 4: Isopropoxyacetic acid

A 500 mL vessel fitted with a mechanical stirrer, thermocouple probe,and nitrogen inlet is charged with 200 mL of IPA (K.F. 220 μg/mL) andsodium hydroxide (6.0 g, 0.145 mol). The mixture was heated at refluxuntil the solid sodium hydroxide dissolved.

A homogeneous solution is obtained after reflux for 3 h.

The solution was cooled at ˜70° C. and toluene (15.0 mL) was added. Itwas distilled until ˜100 mL of distillate was collected. A mixture ofIPA/toluene (85:15, 100 mL) was added and ˜0.1 L of liquid was distilledoff (repeated 3×). At the end of distillation (˜0.4 L of distillatecollected), the solution was diluted with IPA to a volume of ˜300 mL.

The distillate is assayed to determine the amount of water removed. Ifthe water removed is <75% of the theoretical amount (K.F. of IPA+that inNaOH+1 equiv generated), the distillation should be continued. Thesolution was then cooled at 60°-70° C. and sodium chloroacetate (15.9 g,0.134 mol) was added in portions over 5 min. No exotherm is observedduring the addition.

The mixture was heated at reflux for 3 h and a sample of the slurry wastaken for assay.

The reaction is followed by ¹ HNMR. An aliquot (˜0.2 mL) of the mixtureis taken and evaporated to dryness. The residue is dissolved in D₂ O for¹ HNMR measurement. The reaction is considered completed when thestarting material is <3% vs. product.

The reaction was quenched by addition of 60.0 mL of water andconcentrated under reduced pressure (150-200 mBar, 50°-60° C.) until˜250 mL of distillate was collected. More water was added (40.0 mL) andthe solution was distilled at normal pressure until the batchtemperature reached ˜103° C. (˜100 mL of solution left, ˜300 mL ofsolvent removed). The solution was cooled at 10°-20° C. and neutralizedby addition of conc. hydrochloric acid (12.5 mL, 0.15 mol).

External cooling may be needed during the addition of acid. The final pHshould be <2.3, preferably ˜2.

t-Butyl methyl ether (80.0 mL) was added. The aqueous solution wassaturated with sodium chloride (˜9.0 g) and the two-phase mixture wasagitated for 0.5 h at 10°-15° C. The layers were separated and theaqueous layer was back extracted with 2×60.0 mL of t-butyl methyl ether.The organic layers were combined and washed with 2×10.0 mL of saturatedaqueous sodium chloride.

The pH of the 2nd brine wash should be >2.5.

The organic solution was dried over 4A molecular sieves (10.0 g) for 14h and filtered. The sieves were washed with 3×15.0 mL of t-butyl methylether. t-Butyl methyl ether was removed under reduced pressure (˜200mBar, 45°-50° C.). Isopropoxyacetic acid was obtained as a slightlyyellow liquid.

Yield: 11.8 g, 75% yield.

Step A 5: 2-(isopropoxy)acetic acid2-methyl-1-(4-methylsulfonyl)phenyl)propan-1-one-2-yl ester

A 100 mL flask was sequentially charged with dry ethanol (45.0 mL,K.F.<100 μg/mL), isopropoxyacetic acid (2.32 g), diisopropylethylamine(4.85 mL) and the bromosulfone (step A 3)(5.0 g). The mixture is heatedto reflux until the bromosulfone is not detected (HPLC, reaction time12-14 hours).

The reaction is considered complete when the bromosulfone is <0.05 A %vs. product.

After the reaction was complete, the solution was allowed to cool andseeded at 42° C. Crystallization initiated immediately and the mixturewas cooled to 1° C. and aged 1 hr. The product ester is filtered andwashed with ethanol (0° C. 5.0 mL wash). After drying in a vacuum oven,the white crystalline title compound was used as is in the next step.

Yield: 4.15 g.

Step A 6:5,5-Dimethyl-4-(4-methylsulfonylphenyl)-3-(2-propoxy)-5H-furan-2-one

A 1L flask was sequentially charged with dry acetonitrile (320 mL,K.F.<100 μg/mL), isopropyl trifluoroacetate (30.1 g, 0.193 mol), and DBU(36.70 g, 0.24 mol). The solution was stirred at ˜20° C. for 15 min andthe ester from Step A5 (55.0 g, 0.161 mol) was added. The solution washeated at reflux under nitrogen and the progress of the reaction wasfollowed by HPLC.

The reaction is considered complete when the intermediate peaks are <0.2A % vs. product.

After the reaction was complete, the solution was cooled at ˜40° C. andfiltered (1μ in-line capsule). The solution was then concentrated at40°-50° C. under reduced pressure until ˜0.20 L of distillate wascollected. Water (350 mL) was added slowly at ˜45° C. After ˜130 mL ofwater was added, the solution turned cloudy (40°-45° C.) and ˜0.02 g ofcrystalline title compound was added as the seed. The mixture was agedfor 30 min and the remaining water was added. The mixture was aged at˜20° C. for 6 h then filtered. The cake was washed with 2×65 mL of 1:4MeCN/water and 3×65 mL of water. The title product was air dried anddried in vacuo (35° C., 200 mBar).

Yield: ˜48.0 g, 92%.

EXAMPLE 1103-(3-Trifluoromethyl)phenoxy-4-(4-methylsulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 3-trifluoromethylphenol.

¹ H NMR (CD₃ COCD₃) δ 1.79 (6H, s), 3.14 (3H, s), 7.41 (3H, m), 7.55(1H, m), 7.95 (2H, dd, J=2, 6.6 Hz), 8.03 (2H, dd, J=2, 6.7 Hz).

Analysis calculated for C₂₀ H₁₇ F₃ O₅ S: C, 56.34; H, 4.02; Found: C,56.21, H, 4.01.

EXAMPLE 1115,5-Dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(piperidine-1-carbonyl)-5H-furan-2-one

Step 15,5-Dimethyl-4-(4-(methylsulfonyl)phenyl)-2-oxo-2,5-dihydrofuran-3-carboxylicacid ethyl ester

A mixture of 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one (2.87 g, 11.8 mmol), ethyl hydrogen malonate (2.02g, 15.3 mmol), CMC (6.51 g, 15.4 mmol) and DMAP (0.35 g, 2.8 mmol) wasdissolved in 100 mL of CH₂ Cl₂. The mixture was stirred for 14 h at roomtemperature, then DBU (4 mL, 27 mmol) was added, stirred 1 h, thenpartitioned between CH₂ Cl₂ and 1M HCl. The organic layer was washedwith brine, filtered through cotton and evaporated. Purification byflash chromatography (90% ether/Hex) provided 2.50 g of the titlecompound.

¹ H NMR (CD₃ COCD₃) δ 8.09 (2H, m), 7.68 (2H, m), 4.05 (2H, q), 3.16(3H, s), 1.58 (6H, s), 0.96 (3H, t).

Step 25,5-Dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(piperidine-1-carbonyl)-5H-furan-2-one

To a room temperature solution of piperidine (284 mg, 3.33 mmol) in CH₂Cl₂ (5 mL) was added trimethylaluminum (2M in hexane, 1.7 mL, 3.4 mmol).After 15 min, the product from Step 1 (310 mg, 0.92 mmol) was added inone portion and the mixture was heated to reflux for 20 h. The resultingsolution was cooled and poured into 1M HCl (gas evolution). The organiclayer was washed with brine, filtered through cotton and evaporated.Purification by flash chromatography (80% EtOAc/Hex) provided 175 mg ofthe title compound.

¹ H NMR (CD₃ COCD₃) δ 8.08 (2H, m), 7.80 (2H, m), 3.49 (2H, m), 3.35(2H, m), 3.17 (3H, s), 1.65 (6H, s), 1.55 (2H, m), 1.40 (4H, m).

EXAMPLE 1125,5-Dimethyl-3-(2-butoxy)-4-(4-methylsulfonylphenyl)-5H-furan-2-one

Step 15,5-Dimethyl-3-(2-butoxy)-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one

To a suspension of the alcohol of Example 109, Step 1 (300 mg, 1.06mmol) in benzene (20.0 mL) were added 2-iodobutane (300 μL) and Ag₂ CO₃(400 mg, 3.27 mmol). After a period of 4 h at 45° C., the reactionmixture was filtered over celite and washed with CH₂ Cl₂. Afterevaporation, the crude product was purified by flash chromatography (35%EtOAc in Hexane) to give 150 mg of the title compound as a white solid.

¹ H NMR (CD₃ COCD₃) δ 0.09 (3H, t), 1.20 (3H, d), 1.65 (6H, s), 3.20(3H, s), 5.00 (1H, m), 8.00 (4H, s).

EXAMPLE 1135,5-Dimethyl-4-(4-methylsulfonylphenyl)-3-(3-pentoxy)-5H-furan-2-one

Step 1 Pentyl-3-oxyacetic acid

To a solution of 3-pentanol (17.6 g, 200 mmol) in benzene (200 mL) wasadded NaH (6.0 g, 400 mmol). After 1 h at r.t., chloroacetic acid sodiumsalt (25.6 g, 200 mmol) was added to the previous mixture. After aperiod of 2 hr. at reflux, the reaction mixture was pourred in H₂ O andacidified with HCl. The mixture was extracted with CH₂ Cl₂, dried overMgSO₄, filtered over silicic acid (30% EOAc in Hexane). Afterevaporation of the solvents the title compound was purified bydistillation (5.0 g).

Step 2 Pentyl-3-oxyacetic acid 2-methyl-1-(4-methylsulfonylphenyl)propan-1-one-yl ester

The title compound was obtained using similar protocol as described forExample 1 Step 3.

Step 35,5-Dimethyl-4-(4-methylsulfonylphenyl)-3-(3-pentylxy)-5H-furan-2-one

To a solution of the ester of Step 2 (500 mg, 1.35 mmol) in DMF (2.5 mL)was added NaH (50 mg, 1.6 mmol). The reaction mixture was heated gentlyto give an orange mixture. After standard extractive workup procedure(EtOAc), the crude mixture was purified by flash chromatography (35%EtOAc in hexane to afford 115 mg of the title compound by filtration inEt₂ O/hexane.

¹ H NMR (CD₃ COCD₃) δ 0.85 (6H, t), 1.60 (4H, m), 1.65 (6H, s), 3.20(3H, s), 4.90 (1H, quintet), 8.05 (4H, s).

EXAMPLE 1152-(5-Chloro-2-pyridinoxy)-3-(4-methylsulfonylphenyl)-cyclopent-2-enone

Using similar protocol described for Example 29 but using1-(5-chloropyridyl-2-oxy)but-3-en-2-one the title compound was obtained.

¹ H NMR (CD₃ COCD₃) δ 2.50 (2H, t), 2.80 (3H, s), 3.10 (2H, t), 7.10(1H, d), 7.30 (2H, d), 7.80 (2H, d), 7.85 (1H, dd), 8.05 (1H, d).

EXAMPLE 1163-(4-Methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 2-hydroxy-4-methylpyridine.

¹ H NMR(CD₃ COCD₃) δ 1.76(6H, s), 2.36(3H, s), 3.15(3H, s), 6.90(1H, s),6.98(1H, d), 7.89(2H, d), 7.98(1H, d), 8.02(2H, d).

EXAMPLE 117(5R)-3-(3,4-Difluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Step 1:2-(S)-t-butyl-5-(R)-ethyl-4-hydroxy-5-methyl-4-(4-(methylthio)phenyl)-1,3-dioxolan-4-one

To a solution of 4-bromothioanisole (27.3 g, 134 mmol) in 300 ml ofanhydrous THF at -72° C. was added 2.5M n-BuLi in hexanes (54 ml, 135mmol) at such a rate as to maintain the internal temperature below -55°C. and the mixture was stirred at -72° C. for an hour. A solution of2-(S)-t-butyl-5-(R)-ethyl-5-methyl-1,3-dioxolan-4-one (16.8 g, 90 mmol,Tetrahedron, 1984, 40, 1313) in 50 ml of THF was added dropwise and themixture was stirred at -72° C. for 15 minutes. Acetic acid (13 ml) wasthen added slowly and the mixture stirred for another 10 min. at -72° C.The reaction was quenched with 25% aq. NH₄ OAc at -72° C. and allowed towarm up to r.t. The title product was extracted in i-PrOAc, dried overNa₂ SO₄ and purified by flash chromatography on silica with EtOAc/hexane2.5 and 5% to yield 22.4 g (80%) of a white solid.

¹ H NMR (CDCl₃, mixture of 2 diastereoisomers 1.8:1) d 0.58, 1.52, 1.68and 2.05 (2H, 4m), 0.70 and 1.36 (3H, 2s), 0.73 and 0.98 (3H, 2T), 1.00(9H, 2s), 2.47 (3H, 2s), 2.47 and 2.57 (1H, 2s, )H), 4.80 and 5.00 (1H,2s), 7.20 (2H, 2d), 7.45 (2H, 2d).

Step 2: 2-(R)-hydroxy-2-methyl-1-(4-(methylthio)phenyl)-1-butanone

A mixture of the product of step 1 (32.0 g, 103 mmol), p-toluenesulfonicacid (900 mg) and 35 ml of water was heated to reflux for an hour. Thetitle product was extracted in 200 mL of EtOAc and the solution used assuch in the next step.

Step 3:2-(R)-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)-1-butanone-1-one

To the product of Step 2 in 200 ml of EtOAc in an ice bath (to maintainthe temperature of the reaction below 25° C.) was added 100 ml oft-BuOH, 2.3 g of Aliquat 336® and a solution of 73.1 g of Oxone® (238mmol KHSO₅) in 450 ml of water and the mixture was stirred at r.t.overnight. It was then neutralized with 10N NaOH. The title product wasextracted in i-PrOAc, dried over Na₂ SO₄, and purified by flashchromatography on silica with EtOAc/toluene 20 & 40% to yield 23.8 g ofa colorless oil. NMR experiments with the chiral shift reagent Eu (hfc)₃indicated an enantiomeric excess superior than 94%. α!_(D) ²⁵ =-11.2°(c=0.8, CHCl₃).

¹ H NMR (CDCl₃) δ 0.87 (3H, t), 1.57 (3H, s), 1.93 (2H, m), 3.07 (3H,s), 3.53 (1H, s), 8.00 (2H, d), 8.13 (2H, d).

Step 4:(5R)-3-(3,4-Difluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 1, step 4, the titlecompound was prepared from 3,4-difluorophenoxyacetic acid and(2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl-butan-1-one.

α!_(D) =+9.40° (c 0.9, acetone).

¹ H NMR(CD₃ COCD₃) δ 0.95(3H, t), 1.80(3H, s), 2.12(2H, q), 3.18(3H, s),6.95(1H, m), 7.14(1H, m), 7.30(1H, m), 7.95(2H, d), 8.06(2H, d).

EXAMPLE 118(5R)-3-(4-Chlorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 117, the title compoundwas prepared from 4-chlorophenoxyacetic acid and(2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl-butan-1-one.

¹ H NMR(CD₃ COCD₃) δ 0.93(3H, t), 1.78(3H, s), 2.12(2H, q), 3.15(3H, s),7.11(2H, d), 7.35(2H, d), 7.92(2H, d), 8.03(2H, d).

EXAMPLE 1193-(2-Methyl-3-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 3-hydroxy-2-methylpyridine.

¹ H NMR(CD₃ COCD₃) δ 1.77(6H, s),2.48(3H, s), 3.14(3H, s), 7.08(1H, m),7.33(1H, d), 7.93(2H, d), 8.02(2H, d), 8.16(1H, m).

EXAMPLE 1203-(4-Methyl-5-nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

A mixture of3-hydroxy-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one(1.5 g,5.3 mmol, Example 109 step 1), 2-chloro-4-methyl-5-nitropyridine(1.0 g,5.8 mmol) and powdered KOH(300 mg, 5.4 mmol) in DMF(20 mL) was heated at100° C. for 12 h. After cooling to r.t., the mixture was diluted with H₂O, extracted with EtOAc. The EtOAc extract was washed with brine,dried(anhydrous MgSO₄) and concentrated in vacuo. The residue wasswished with EtOH to give the title compound as a pale yellow solid(1.7g, 77%).

¹ H NMR (CD₃ COCD₃) δ 1.80(6H, s), 2.68(3H, s), 3.16(3H, s), 7.20(1H,s), 7.90(2H, d), 8.05(2H, d), 8.85(1H, s).

EXAMPLE 1213-(5-Chloro-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Step 1:3-(5-Amino-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

A mixture of3-(4-methyl-5-nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one(1.4g, 3.3 mmol), iron powder(1.5 g, 27 mmol) and NH₄ Cl(150 mg) in 67%aqueous EtOH(45 mL) was refluxed for 1 h. The hot mixture was filteredthrough celite. Volatile solvent was evaporated in vacuo. The residuewas suspended in water, filtered and dried under vacuum to give thetitle compound as a brown powder(1.2 g, 94%).

¹ H NMR (CD₃ COCD₃) δ 1.72(6H, s), 2.20(3H, s), 3.15(3H, s), 4.42(2H,brs), 6.75(1H, s), 7.50(1H, s), 7.90(2H, d), 8.00(2H, d).

Step 2:3-(5-Chloro-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-4H-furan-2-one

To a suspension of3-(5-amino-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one(600mg, 1.6 mmol) in 6M aqueous HCl(3 mL) at 0° C. was added dropwise asolution of 4M aqueous NaNO₂ (450 mL, 1.8 mmol). The solution becameclear and then precipitate formed. After stirring for 30 min, thediazotization mixture was added to a solution of CuCl(300 mg, 3.0 mmol)in concentrated HCl(2 mL) at 0° C., then heated to 70°-80° C. for 10min, cooled to r.t. and diluted with H₂ O and dried under vacuum.Recrystallization from EtOH-Acetone yielded the title compound as alight yellow solid(360 mg, 57%).

¹ H NMR (CD₃ COCD₃) δ 1.76(6H, s), 2.40(3H, s), 3.16(3H, s), 7.10(1H,s), 7.90(2H, d), 8.05(2H, d), 8.10(1H, s).

EXAMPLE 1223-(5-Fluoro-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

To a suspension of3-(5-amino-4-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one(650mg, 1.68 mmol, Example 121 step 1) in 6M aqueous HCl(4 mL) at 0° C. wasadded dropwise a solution of 4M aqueous NaNO₂ (450 mL, 1.8 mmol). Afterstirring at 0° C. for 30 min, 60% aqueous HPF₆ (2 mL) was added and themixture was further stirred for 30 min. The precipitate was collected,washed with H₂ O and dried under vacuum to give 850 mg of diazoniumsalt.

The diazonium salt was then heated with a propane torch until thecompound started to decompose. The dark brown residue was dissolved inacetone and chromatographed over silica gel, eluted withhexanes:EtOAc(2:3) to provide the title compound as a pale yellowsolid(100 mg, 17%).

¹ H NMR (CD₃ COCD₃) δ 1.72(6H, s), 2.34(3H, s), 3.16(3H, s), 7.02(1H,m), 7.90(2H, d), 7.94(1H, s), 8.02(2H, d).

EXAMPLE 1233-(3-Chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Step 1:3-(3-Nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

A mixture of3-hydroxy-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one(1.5 g,5.3 mmol), 2-chloro-3-nitropyridine(1.0 g, 6.3 mmol) and powderedKOH(320 mg, 5.7 mmol) in DMF(20 mL) was heated at 100° C. for 12 h.After cooling to r.t., the mixture was diluted with H₂ O, extracted withEtOAc. The EtOAc extract was washed with brine, dried(anhydrous MgSO₄)and concentrated in vacuo. Chromatography over silica gel and elutionwith hexanes:EtOAc(1:1) gave a solid residue. The residue was swishedwith EtOH to provide 1.6 g(73%) of title compound.

¹ H NMR (CD₃ COCD₃) δ 1.82(6H, s), 3.18(3H, s), 7.50(1H, m), 8.00(4H,m), 8.50(1H, m), 8.60(1H, d).

Step 2:3-(3-Amino-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

A mixture of3-(4-methyl-4-nitro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one(1.5g, 3.7 mmol), iron powder(1.5 g, 27 mmol) and NH₄ Cl(150 mg) in 67%aqueous EtOH(45 mL) was refluxed for 1 h. The hot mixture was filteredthrough celite. Volatile solvent was evaporated in vacuo. The residuewas suspended in water, filtered and dried under vacuum to give thetitle compound as a brown powder(1.4 g, quantitative).

¹ H NMR (CD₃ COCD₃) δ1.76(6H, s), 3.18(3H, s),4.88(2H, brs), 6.86(1H,m), 7.10(1H, m), 7.35(1H, m), 7.98(4H, m).

Step 3:3-(3-Chloro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one

To a suspension of3-(3-amino-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one(700mg, 1.7 mmol) in 6M aqueous HCl(3 mL) at 0° C. was added dropwise asolution of 4M aqueous NaNO₂ (500 mL, 2.0 mmol). After stirring for 30min, the diazotization mixture was added to a solution of CuCl(400 mg,4.0 mmol) in concentrated HCl(2 mL) at 0° C., then heated to 70°-80° C.for 10 min, cooled to r.t., diluted with H₂ O and extracted with EtOAc.Chromatography over silica gel and elution with hexanes:EtOAc(1:1) togive a solid residue(100 mg). Recrystallization from EtOH provided thepure title compound(90 mg, 13%).

¹ H NMR (CD₃ COCD₃) δ 1.80(6H, s), 3.16(3H, s), 7.20(1H, m), 7.94(2H,d), 7.98(1H, m), 8.05(2H, d), 8.10(1H, m).

EXAMPLE 1243-(4-Fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-propyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl-1-pentanoneand 4-fluorophenol.

¹ H NMR(CD₃ COCD₃) δ 0.94(3H, t), 1.38(2H, m), 1.78(3H, s), 2.05(2H, m)3.14(3H, s), 7.08(4H, m), 7.92(2H, d), 8.02(2H, d).

EXAMPLE 125 3-(Diethylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Step 1: 2-(diethyl amino)acetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one-2-yl ester

To a room temperature solution of 2-chloroacetic acid2-methyl-1-(4-methylsulfonyl)phenyl)propan-1-one-2-yl ester (2.00 g,6.27 mmol) in acetonitrile (10 mL) was added diethyl amine (1.62 mL,15.7 mmol). The resulting solution was heated to 60° C. for 16 hours.The reaction mixture was cooled to room temperature and partitionedbetween dichloromethane and water. The organic layer was separated,washed with brine, filtered through cotton and the solvent wasevaporated under vacuum. Purification by silica gel chromatography (80%EtOAC/Hex.) provided 1.70 g of the title compound.

¹ H NMR (CD₃ COCD₃) δ 0.85 (6H,t), 1.70 (6H, s), 2.37 (4H, q), 3.15(3H,s) 3.27 (2H,s), 8.00-8.07 (2H,m), 8.15-8.22 (2H,m).

Step 2: 3-(Diethylamino)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Sodium hydride, 60% dispersion (0.478 g, 11.96 mmol) was washed inhexane and suspended in DMF (5 mL). This suspension was added to a 0° C.solution of 2-(diethyl amino)acetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one-2-yl ester (1.70 g,4.78 mmol) in DMF (20 mL). The resulting mixture was warmed to RT for 15minutes. The mixture was diluted with ethyl acetate and quenched withwater. The organic layer was washed with brine, dried over MgSO₄ andconcentrated to dryness. The residue was purified by swishing inether/hexanes to give 500 mg of crystalline solid on filtration.

¹ H NMR (CD₃ COCD₃) δ 0.95 (6H, t), 1.45 (6H,s), 3.07 (4H,q), 3.17(3H,s), 7.65-7.70 (2H,m), 7.97-8.05 (2H,m).

EXAMPLE 1275,5-dimethyl-4-(4-methylsulfonyl-phenyl)-3-(3,5-dichloro-pyridin-2-yloxy)-5H-furan-2-one

To a R.T. solution of 2-chloroacetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (954 mg, 3 mmol,example 25) in acetonitrile (15 mL) was added 3,5-dichloro-2-pyridone(656 mg, 4.0 mmol) followed by DBU (2.28 g, 15 mmol) and the mixture wasslowly warmed up to gentle reflux for 2 hours. The mixture was cooled to25° C. the volatiles were removed in vacuo. The residue was purified onsilica gel chromatography (1/1, EtOAc/Hexanes then 100% EtOAc)) toprovide the title compound.

Analysis calculated for C₁₈ H₁₅ Cl₂ NO₅ S: C, 50.48; H, 3.53; N, 3.27.Found: C, 50.53; H, 3.49; N, 3.21.

EXAMPLE 128(5R)-3-(4-Bromophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 117, the title compoundwas prepared from 4-bromophenoxyacetic acid and(2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenylbutan-1-one.

¹ H NMR(CD₃ COCD₃) δ 0.93(3H, t), 1.78(3H, s), 2.12(2H, q), 3.15(3H, s),7.05(2H, d), 7.50(2H, d), 7.94(2H, d), 8.05(2H, d).

EXAMPLE 129(5R)-3-(4-Methoxyphenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from(2R)-2-chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenylbutan-1-one(prepared similarly to the compound of Example 5 step 1) and4-methoxyphenol.

¹ H NMR(CD₃ COCD₃) δ 0.92(3H, t), 1.75(3H, s), 2.08(2H, q), 3.14(3H, s),3.74(3H, s), 6.83(2H, d), 6.97(2H, d), 7.89(2H, d), 7.99(2H, d).

EXAMPLE 130(5R)-3-(5-Chloro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one

Step 1:2-(S)-t-butyl-5-(R)-methyl-5-(2,2,2-trifluoroethyl)-1,3-dioxolan-4-one

To a solution of lithium diisopropylamide (prepared from 13 ml ofdiisopropylamine and 54 ml of 1.6M n-BuLi in hexanes in 200 ml ofanhydrous THF at 0° C.) at -72° C. was added slowly2-(s)-t-butyl-5-(s)-methyl-1,3-dioxolan-4-one (12.95 g, 81.9 mmol,Tetrahedron, 1984, 40, 1313) at such a rate as to maintain the internaltemperature below -60° C. and the mixture was aged at -72° C. for anhour. 1,1,1-Trifluoro-2-iodoethane (25 g, 119 mmol) was added quickly,the reaction temperature increased to -45° C. and the mixture was agedat -72° C. for 45 min. and then allowed to warm up to -20° C. over 20min. Saturated aq. NH₄ Cl was then added and the product was extractedin i-PrOAc, dried over Na₂ SO₄, concentrated and distilled under reducedpressure to afford 7.51 g of a brown oil BP 90° C./20 mm Hg.

¹ H NMR (CDCl₃, mixture of distereoisomers 3.2:1) d 0.97 (9H, 2s), 1.50and 1.54 (3H, 2s), 2.59 (2H, m), 5.22 (1H, 2d).

Step 2:2-(R)-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)-4,4,4-trifluoro-1-butanone

Using the procedures of Example 117 step 1, 2 and 3, the product of Step1 was converted to the title compound.

¹ H NMR (CDCl₃) δ 1.68 (3H, s), 2.72 (1H, m), 2.98 (1H, m), 3.08 (3H,s), 3.35 (1H, br s, OH), 8.03 (2H, d), 8.14 (1H, d).

Step 3:(2R)-2-Chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenyl-4,4,4-trifluoro-butan-1-one

A mixture of(2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl-4,4,4-trifluoro-1-butanone(5.2g, 16.8 mmol), chloroacetic acid(2.0 g, 21 mmol), CMC(9.5 g, 22 mmol)and DMAP(100 mg) in CH₂ Cl₂ (50 mL) was stirred at r.t. for 2 h. TLCshowed the esterification completed. The mixture was washed with H₂O(2×), dried(anhydrous MgSO₄) and concentrated in vacuo. Chromatographyover silica gel and elution with hexanes:EtOAc(1:1) gave 6.0 g(92%) ofthe title compound as an oil.

¹ H NMR(CD₃ COCD₃) δ 1.98(3H, s), 3.18(3H, s), 3.28(2H, m), 4.35(2H, m),8.08(2H, d), 8.28(2H, d).

Step 4:(5R)-3-(5-Chloro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from(2R)-2-chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenyl-4,4,4-trifluoro-butan-1-oneand 5-chloro-2-pyridinol.

¹ H NMR(CD₃ COCD₃) δ 1.94(3H, s), 3.16(3H, s), 3.24(2H, q), 7.20(1H, d),7.95(1H, m), 7.98(2H, d), 8.04(2H, d), 8.16(1H, m).

EXAMPLE. 1333-(5-Chloro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-propyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from2-chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenyl-1-pentanone(prepared in a fashion similar to that of the compound in example 1 step1,2 and 3) and 5-chloro-2-pyridinol.

¹ H NMR(CD₃ COCD₃) δ 0.93(3H, t), 1.42(2H, m), 1.76(3H, s), 2.05(2H, m)3.15(3H, s), 7.16(1H, d), 7.90(3H, m), 8.02(2H, d), 8.16(1H, m).

EXAMPLE 134 3-(1-Cyclopropyl-ethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one

Step 1: (1-cyclopropyl-ethoxy)acetic acid

To a suspension of NaH (80% in oil) (15.7 g, 523 mmol) in THF (180 mL)at 0° C. were added bromoacetic acid (28.0 g, 203 mmol) anda-methylcyclopropane methanol (10.0 g, 116 mmol). The resulting mixturewas then stirred at 70° C. After a period of 18 h, the reaction mixturewas poured over cold H₂ O and the H₂ O phase was extracted once with Et₂O. The water phase was acidified with HCl and extracted twice with Et₂O. The ether was dried over MgSO₄, filtered and evaporated under reducedpressure. The crude oil was then purified by flash chromotography (40%EtOAc in hexane to 40% EtOAc in Hexane+AcOH) to provide 5.0 g of thetitle compound.

Step 2: 2-(1-Cyclopropylethoxy)acetic acid2-methyl-1-(4-methylsulfonyl)phenyl)propan-1-one-2-yl ester

A mixture of (1-cyclopropyl-ethoxy)acetic acid (1.0 g, 6.90 mmol;Example 134, Step 1)2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one (1.37 g,5.76 mmol; Example 1, Step 3), CMC (8.90 g, 20.8 mmol) and DMAP (100 mg,0.820 mmol) in CH₂ Cl₂ (100 ml) was left at r.t. for a period of 18 h.The resulting mixture was partitioned between NH₄ OAc (20%) and CH₂ Cl₂.The organic phase was dried over MgSO₄, filtered and evaporated underreduced pressure. The resulting mixture was purified by flashchromatography (35% EtOAc in hexane) to provide 590 mg of the titlecompound.

Step 3:3-(1-Cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one

To a solution of 2-(1-cyclopropyl-ethoxy)acetic acid2-methyl-1-(4-(methyl sulfonyl)phenyl)propan-1-one-2-yl ester (590 mg,1.60 mmol; Example 134, Step 2) CH₃ CN (20 mL) were added isopropyltrifluoro acetate (294 mL, 2.07 mmol) and DBU (782 mg, 5.14 mmol). Aftera period of 18 h at 70° C. The reacting mixture was evaporated underreduced pressure and purified by flash chromatography (30% EtOAc intoluene) to provide 270 mg of the title compound.

¹ H NMR (CD₃ COCD₃) δ 0.20 to 0.50 (5H, m), 0.90 (1H, m), 1.35 (3H, d),1.65 (6H, s), 3.20 (3H, s), 4.35 (1H, quintet), 8.10 (4H, m).

EXAMPLE 136 5-Methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-(propoxy)-5-(2,2,2-trifluoroethyl)-5H-furan-2-one

Following the procedure described for Example 109, using2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl)-4-trifluorobutan-1-onethe title compound was obtained.

Step 2:3-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl-5-(2-trifluoroethyl)-5H-furan-2-one

¹ H NMR (CD₃ COCD₃) δ 1.30 (6H, 2d), 1.80 (3H, s), 3.15 (3H, s), 3.15 to3.40 (2H, m), 5.30 (1H, quintet), 8.10 (4H, m).

EXAMPLE 1405(R)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-propoxy)-5H-furan-2-one

The title compound was prepared as described in Example 109, Step 2using(5R)-5-ethyl-3-hydroxy-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one,which was prepared from the compound of Example 117, Step 3 followingthe procedure of Example 109, Step 1.

¹ H NMR (CD₃ COCD₃) δ 0.80 (6H, 2d), 1.60 (3H, s), 2.00 (2H, m), 3.15(3H, s), 5.20 (1H, quintet), 8.00 (4H, s).

EXAMPLE 1415,5-Dimethyl-3-(2,2-dimethylpropyloxy)-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

To a mixture of5,5-dimethyl-3-hydroxy-4-(4-(methylsulfonyl)phenyl-5H-furano2-one (500mg, 1.77 mmol, Example 109, Step 1) in DMF (6 mL) were added NaH (65 mg,1.2 eq.), and neopentyl iodide (585 μL). After a period of 18 h at 70°C., the reaction mixture was diluted with EtOAc. The mixture was washedwith H₂ O and the organic phase separated, dried over MgSO₄ andevaporated under reduced pressure. The resulting oil was purified byflash chromatography to provide the title compound (124 mg) as a whitesolid after precipitation with Et₂ O.

¹ H NMR (CD₃ COCD₃) δ 0.95 (9H, s), 1.65 (6H, s), 3.15 (3H, s), 4.00(2H, s), 8.00 (4H, m).

EXAMPLE 143 5(R)3-(1-cyclopropyl-ethoxy)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl-5H-furan-2-one

Step 1: (1-cyclopropylethoxy)acetic acid2(R)-methyl-1-(4-(methylsulfonyl)phenyl)butan-1-one-2yl ester

The title compound was prepared as described in Example 134 Step 2 using(1-cyclopropylethoxy)acetic acid and 2(R)2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)butan-1-one from Example117, Step 3.

Step 2:5(R)3-(1-cyclopropylethoxy)-5-ethyl-5-methyl-4(4-(methylsulfonyl)phenyl-5H-furan-2-one

The title compound was prepared as described in Example 134 Step 3.

¹ H NMR (CD₃ COCD₃) δ 0.1-0.4 (4H, m), 0.75 (2H, m), 1.00 (1H, m), 1.40(3H, dd), 1.70 (3H, s), 2.05 (2H, m), 3.20 (3H, s), 4.50 (1H, m), 8.05(m, 4H).

EXAMPLE 1445(S)5-Ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl-3-(2-propoxy)-5H-furan-2-one

Step 1: (±)2-Methyl-1-(4-methylsulfonylphenyl)-prop-2-en-1-ol

To a solution of 4-bromothioanisole (51 g) in THF (600 mL) cooled to-72° C. was added dropwise a solution of n-BuLi (120 mL, 2.4M in hexane)over a period of 30 min. The mixture was stirred at -78° C. for 2 h andthen a solution of methacrolein (20.3 g) in THF (50 mL) was added over aperiod of 5 min. The reaction mixture was warmed to -20° C. over aperiod of 20 min. and then quenched with saturated NH₄ Cl (200 mL) andH₂ O (200 mL). The product was extracted with 500 mL of 1:1hexane/EtOAc, and dried over MgSO₄. The extract was filtered andconcentrated to give the title compound as a yellow oil (55 g).

Step 2: (±)2-Methyl-1-(4-methylsulfonylphenyl)-prop-2-en-1-ol

To a solution of the product from Step 1 (55 g., crude) in MeOH (1 L)cooled to 0° C. was added a solution of Oxone® (190 g in 700 mL H₂ O)over a period of 2 h. The mixture was stirred at 5° C. for an additional3 h and then filtered. The filtrate was concentrated to remove MeOH andthe remaining aqueous mixture was extracted with 1 L of 2:1EtOAc/hexane. The extract was dried over MgSO₄ filtered andconcentrated. The residue was purified by silica gel chromatographyeluted with 3:2 hexane/EtOAc to give the title compound (22 g) as acolorless oil.

Step 3: (S)-2-Methyl-1-(4-methylsulfonylphenyl)-prop-2-en-1-ol

To a solution of dry 4A molecular sieves (20 g), and Ti(O₂ Pr)₄ (24.8mL) in CH₂ Cl₂ (1 L) cooled to -25° C. was added dropwise(+)-diisopropyltartrate (22.4 mL). After stirring at -25° C. for 30min., a solution of(±)-2-methyl-1-(4-methylsulfonylphenyl)-prop-2-en-1-ol (21 g) in 500 mLof CH₂ Cl₂ was added dropwise, followed by a solution of t-butylhydroperoxide (20 mL, 5M in decane). The reaction mixture was stirred at-25° C. for 5 h and then quenched with 500 mL of 10% aqueous solution oftartaric acid. After stirring for 1 h, the CH₂ Cl₂ layer was separated,dried over MgSO₄ and concentrated. The residue was purified by silicagel chromatography eluted first with 3:1 hexane/EtOAc followed by 1:2hexane/EtOAc to give the title compound as a white solid (9 g).

Step 4: (R)-(2-Methyloxiran-2-yl)-(4-methanesulfonylphenyl)methanol

Following the same procedure described in Step 3 using 15 g of 4Amolecular sieves, 500 mL of CH₂ Cl₂, 12.4 mL of Ti(OiPr)₄, 11.2 mL of(-)-diisopropyl tanrate, 20 mL of 5M tBuOOH in decane and 9.8 g of theproduct from Step 3, the title compound (7.6 g, white solid) wasobtained.

Step 5: (R)-(1-Ethoxy-ethoxy)-(4-methanesulfonylphenyl)-methyl!-2-methyloxirane

To a solution of the product from Step 4 (7.2 g) and ethylvinyl ether(50 mL) in 200 mL of CH₂ Cl₂ cooled to 0° C. was added 50 mg ofcamphorsulfonic acid. The reaction mixture was stirred at r.t. for 20min. and then treated with 1 mL of Et₃ N, concentrated to give the crudetitle compound (9 g).

Step 6:(R,S)-1-(1-Ethoxy-ethoxy)-2-methyl-1-(4-methylsulfonylphenyl)-butan-2-ol

To a suspension of CuI(20 g) in EtO (450 mL) cooled at -40° C. was addeddropwise a solution of MeLi (150 mL, 1.4M in Et₂ O). After stirring at-40° C. for 20 min., a solution of the crude product from Step 7 (9 g)in 50 mL of Et₂ O was added. The reaction mixture was stirred at -40° C.for 30 min. and then quenched with 20 mL of MeOH and 300 mL of saturatedNH₄ Cl solution. Air was bubbled into the mixture with stirring at r.t.for 1 h. The resulting mixture was then extracted with 400 mL of Et₂ Oand the Et₂ O extract was dried over MgSO₄ and concentrated to give thecrude title compound (10 g) which was used for next step without furtherpurification.

Step 7: (R.S)-2-Methyl-1-(4-methylsulfonylphenyl)-butane-1,2-diol

A solution of the crude product from Step 8 (10 g) in 200 mL of THF, 50mL of AcOH and 50 mL of H₂ O was heated at 50° C. for 15 h. The mixturewas then concentrated to give the crude title compound (7 g) which wasused for next step with further purification.

Step 8: (S)-2-Hydroxy-2-methyl-1-(4-methylsulfonylphenyl)-butan-1-one

To a solution of the crude product from Step 7 (7 g) and (Bu₃ Sn)₂ O (30mL) in 150 mL of CH₂ Cl₂ cooled at 10° C. was added a solution of Br₂(9.3 g in 30 mL of CH₂ Cl₂). After stirring at r.t. for 30 min. themixture was diluted with a solution of KF (500 mL, 3N) and 500 mL of Et₂O. The solid generated was removed by filtration and the filtrate wasseparated. The organic layer was dried over MgSO₄ and concentrated. Theresidue was purified by silica gel chromatography eluted with 1:1hexane/EtOAc to give 5 g of the title compound as a yellow oil.

¹ H NMR (acetone-d₆) δ 8.31 (2H, d), 8.00 (2H, d), 4.67 (1H, s), 3.18(3H, s), 2.00 (1H, m), 1.30 (1H, m), 1.50 (3H, s), 0.90 (3H, t).

Step 9:5(S)5-ethyl-S-methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-propoxy)-5H-furan-2-one

The title compound was prepared as described in Example 1 Step 4 using2-propoxyacetic acid and2(S)2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)butan-1-one.

¹ H NMR (CD₃ COCD₃) δ 0.80 (3H, t), 1.30 (6H, t), 1.70 (3H, s), 2.10(2H, m), 3.20 (3H, s), 5.25 (1H, m), 8.05 (4H, m).

EXAMPLE 146 AND 147 3-(1-cyclopropylethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one (146) and3-(1-cyclopropylethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one(147)

The racemate of Example 134 was separated on a HPLC CHIRALPAK AD(Daicel) column with 10% isopropanol in hexane.

EXAMPLE 1483-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl-5H-furan-2-one

Step 1:3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl-5H-furan-2-one

The title compound was prepared as described in Example 141 using5,5-dimethyl-3-hydroxy-4-(4-(methylsulfonyl)phenyl-5H-furan-2-one and(bromomethyl)cyclopropane.

¹ H NMR (CD₃ COCD₃) δ 0.30 (2H, m), 0.55 (2H, m), 1.15 (1H, m), 1.60(6H, s), 3.20 (3H, s), 4.20 (2H, d), 8.00 (4H, s).

EXAMPLE 1495,5-dimethyl-3-(isobutoxy)-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

The title compound was prepared as described in Example 141 using5,5-dimethyl-3-hydroxy-4-(4-(methylsulfonyl)phenyl-5H-furan-2-one and1-bromo-2-methylpropane.

¹ H NMR (CD₃ COCD₃) δ 0.90 (6H, d), 1.65 (6H, d), 1.95 (1H, m), 3.20(3H, s), 4.10 (2H, d), 8.00 (4H, m).

EXAMPLE 1503-(4-Bromophenoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 1, the title compound wasprepared from bromophenoxy acetic acid.

M.P.: 150°-152° C. ¹ H NMR (CD₃ COCD₃) δ 1.77 (6H, s), 3.15 (3H, s),7.07 (2H, d), 7.46 (2H, d), 7.92 (2H, d), 8.02 (2H, d).

EXAMPLE 533-(6-Amino-2-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 2-hydroxy-6-aminopyridine.

M.P.: 165°-166° C. ¹ H NMR (CD₃ COCD₃) δ 1.74 (6H, s), 3.14 (3H, s),5.52 (2H, s, br), 6.17 (1H, d), 6.24 (1H, d), 7.41 (1H, t), 7.90 (2H,d), 8.02 (2H, d).

EXAMPLE 313-(2-Quinolinoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 2-hydroxyquinoline. M.P.: 141°-142° C.

¹ H NMR (CD₃ COCD₃) δ 1.83 (6H, s), 3.11 (3H, s), 7.26 (1H, m), 7.52(1H, m), 7.70 (1H, m), 7.77 (1H, m), 7.93-8.02 (5H, m), 8.39 (1H, s).

EXAMPLE 503-(2-Chloro-5-pyridyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared using 2-chloro-5-hydroxypyridine.

M.P.: 196°-197° C.

¹ H NMR (CD₃ COCD₃) δ 1.78 (6H, s), 3.16 (3H, s), 7.33 (1H, m), 7.68(1H, m), 7.94 (2H, d), 8.04 (2H, d), 8.14 (1H, m).

EXAMPLE 1593-(6-benzothiazolyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 6-hydroxybenzothiazole M.P.: 212° C.

¹ H NMR (CD₃ COCD₃) δ 1.79 (6H, s), 3.10 (3H, s), 7.34 (1H, s), 7.86(1H, d), 7.93-8.00 (5H, m), 9.15 (1H, s).

EXAMPLE 1603-(6-Chloro-2-pyridiloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 6-chloro-2-hydroxypyridine M.P.: 119°-121° C.

¹ H NMR (CD₃ COCD₃) d 1.78 (6H, s), 3.15 (3H, s), 7.10 (1H, d), 7.25(1H, d), 7.89-8.06 (5H, m).

EXAMPLE 1613-(4-Quinazolyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 4-hydroxyquinazoline. M.P.: 174°-177° C.

¹ H NMR (CD₃ COCD₃) δ 1.76 (6H, s), 3.12 (3H, s), 7.58 (1H, t), 7.67(1H, d), 7.76 (2H, d), 7.85 (1H, t), 8.03 (2H, d), 8.16 (1H, d), 8.22(1H, s).

EXAMPLE 162(5R)-3-(5-Fluoro-2-pyridyloxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from(2R)-2-chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenylbutan-1-one(prepared similarly to the compound of Example 5, Step 1 but using the2-(R) compound of Example 117, Step 3) and 5-fluoro-2-hydroxy-pyridine.M.S.: (CI, CH4) m/z 392 (M+H)⁺

¹ H NMR (CD₃ COCD₃) δ 0.95 (3H, t), 1.76 (3H, s), 2.12 (2H, m), 3.15(3H, s), 7.18 (1H, m), 7.73 (1H, m), 7.91 (2H, d), 8.02-8.07 (3H, m).

EXAMPLE 163(5R)-3-(4-Fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described in Example 1, Step 4, the titlecompound was prepared using(2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenylbutan-1-one (Example117, Step 3) and 4-fluorophenoxy acetic acid. M.P.: 96.8°-97.4° C.

¹ H NMR (CD₃ COCD₃) δ 0.92 (3H, t), 1.77 (3H, s), 2.11 (2H, q), 3.14(3H, s), 7.08-7.11 (4H, m), 7.9 (2H, d), 8.02 (2H, d).

EXAMPLE 164(5R)-3-(5-Fluoro-2-pyridyloxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from(2R)-2-chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenyl-4,4,4-trifluorobutan-1-one(Example 130, Step 3) and 5-fluoro-2-hydroxypyridine.

¹ H NMR (CD₃ COCD₃) δ 1.94 (3H, s), 3.15 (3H, s), 3.24 (2H, q), 7.20(1H, m), 7.75 (1H, m), 7.98-8.07 (5H, m).

EXAMPLE 1653-(1-Isoquinolinyloxy)-5,5-dimethyl-4-(methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared using 1-hydroxyisoquinoline.

M.P.: 193.5-194.5

¹ H NMR (CD₃ COCD₃) δ 1.75 (6H, s), 3.12 (3H, s), 6.57 (1H, d), 7.27(1H, d), 7.50-7.76 (5H, m), 8.02 (2H, d), 8.24 (1H, d).

EXAMPLE 166(5R)-3-(4-fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one

Following the procedure described in Example 1, Step 4, the titlecompound was prepared using2-(R)-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)-4,4,4-trifluoro-1-butanone(Example 130, Step 2) and 4-fluorophenoxyacetic acid. M.P.:104.7°-107.0° C.

¹ H NMR (CD₃ COCD₃) δ 1.94 (3H, s), 3.15 (3H, s), 3.27 (2H, m),7.07-7.13 (4H, m), 7.98-8.04 (4H, m), M.S.: (CI, CH₄) m/z 463 (M+H)⁺

EXAMPLE 1673-(3-Fluoro-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 5, the title compound wasprepared using 3-fluoro-2-hydroxypyridine M.P.: 156°-157° C.

¹ H NMR (CD₃ COCD₃) δ 1.78 (6H, s), 3.14 (3H, s), 7.23 (1H, m), 7.72(1H, m), 7.91 (2H, d), 7.96 (1H, d), 8.03 (2H, d).

EXAMPLE 168(5R)-3-(3,4-difluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from(2R)-2-chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenyl-4,4,4-trifluorobutan-1-one(Example 130, Step 3) and 3,4-difluorophenol.

EXAMPLE 169(5R)-3-(5-chloro-2-pyridyloxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

To a solution of2-(R)-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)-1-butanone (800 mg,30 mmol), Example 117, Step 3, in 24 mL of acetonitrile was addedchloroacetic acid (383 mg), CMC (1.7 g) and DMAP (20 mg). The mixturewas then stirred at r.t. for 4 hours. Then 5-chloro-2-hydroxypyridine(602 mg) and DBU (1.85 mL) were added and the mixture was stirred for 18hours. Water was then added to the mixture which was extracted with CH₂Cl₂, then washed with 1N Hcl, brine, dried over MgSO₄, filtered and thesolvent evaporated under vacuum purification by flash chromatography onsilica gel 40% EtOAc/Hexane afforded the title compound. M.P.: 191° C.

¹ H NMR (CD₃ COCD₃) δ 0.95 (3H, t), 1.76 (3H, s), 2.11 (2H, m), 3.15(3H, s), 7.18 (1H, d), 7.89-7.93 (3H, m), 8.03 (2H, d), 8.16 (1H, d).

EXAMPLE 1703-(3,4-difluorophenoxy)-5-methyl-5-trifluoromethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Step 1: 2-Trifluoromethyl-2-trimethylsilyloxypropionitrile

A mixture of 1,1,1-trifluoroacetone (8.9 mL, 0.1 mmol),trimethylsilylcyanide (13.3 mL, 0.1 mmol) and zinc iodide (5 mg) wasstirred for 18 hours, to afford the title compound.

Step 2: 2-Hydroxy-1-(4-methylthio)phenyl-2-trifluromethyl propanone

To a solution of 4-bromothioanisole (19 g, 94 mmol) in THF (200 mL) at-78° C. was added 1.33M n-Butyl lithium (71 mL, 94 mmol). The mixturewas stirred for 1 hr at -78° C. then 10 g (47 mmol) of the compound fromStep 1 was added and the mixture was left to warm to r.t. The reactionmixture was quenched with 25% NH₄ OAc extracted with EtOAc, washed withbrine, dried over MgSO₄, filtered and the solvent evaporated to afford9.7 g of the title compound.

Step 3: 2-Hydroxy-1-(4-methylsulfonyl)phenyl-2-trifluoromethyl propanone

Following the procedure described in Example 117, Step 3, and using thecompound from the previous step, the title compound was obtained.

Step 4:3-(3,4-difluorophenoxy)-5-methyl-5-trifluoromethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described in Example 1, Step 4, and using thecompound obtained in the previous step, the title compound was obtained.M.P.: 154.1° C.

¹ H NMR (CD₃ COCD₃) δ 2.06 (3H, s), 3.15 (3H, s), 6.98 (1H, s) 7.7 (1H,m), 7.26 (1H, dd), 7.77 (2H, d), 8.02 (2H, d).

EXAMPLE 1713-(3,4-Difluorophenoxy)-5-methyl-4-(4-(methylsulfonyl)phenyl)-5-propyl-5H-furan-2-one

Step 1: 2-Methyl-1-(4-methylthiophenyl)-pentan-1-one

Following the procedure described for Example 1, Step 1, the titlecompound was prepared from 2-methyvaleryl chloride and thioanisole.

Step 2: 2-Hydroxy-2-methyl-1-(4-methylthiophenyl)-pentan-1-one

Following the procedure described for Example 1, Step 2, the titlecompound was prepared from the product obtained in Step 1.

Step 3: (3,4-Difluorophenoxy)-acetic acid1-methyl-1-(4-methythiobenzoylbutyl)ester

A solution of 3,4-difluorophenoxyacetic acid (0.38 g), the product fromStep 2 (0.24 g), CMC (1.0 g), and DMAP (100 mg) in 5 mL of CH₂ Cl₂ wasstirred at r.t. for 15 h. The reaction mixture was then treated withsaturated solution of NaHCO₃ (20 mL) and extracted with 1:1 EtOAc/hexane(100 mL). The organic layer was dried over MgSO₄ filtered andconcentrated to give the crude product which was used for next stepwithout further purification.

Step 4: (3,4-Difluorophenoxy)-acetic acid1-methyl-1-(4-methysulfonylbenzoylbutyl ester

A solution of the crude product from Step 3 in 50 mL of 10:1 CH₂ Cl₂/MeOH (v/v) was treated with MMPP (1.0 g). The mixture was stirred atr.t. for 30 min. and then diluted with saturated NaHCO₃ solution (50mL). The mixture was extracted with EtOAc (50 mL) and the organic layerwas dried over MgSO₄, filtered and concentrated to give the titlecompound as a white solid.

Step 5:3-(3,4-Difluorophenoxy)-5-methy-4-(4-(methylsulfonyl)phenyl)-5-propyl-5H-furan-2-one

A solution of the product from Step 4, CF₃ CO₂ iPr (0.5 mL) and DBU (0.2mL) in CH₃ CN (30 mL) was heated to reflux for 30 min. The mixture wasthen cooled to r.t. treated with ACOH (1 mL) and concentrated. Theresidue was dissolved in 2:1 EtOAc/hexane (20 mL) and filtered through apad of silica gel. The filtrate was concentrated and the residue wasstirred at 5° C. 5:1 hexane/EtOAc (10 mL) for 15 h. The title compoundwas isolated by filtration as a white solid (380 mg).

¹ H NMR (acetone-d₆) δ 8.04 (2H, d), 7.93 (2H, d), 7.28 (1H, m), 7.12(1H, m), 6.92 (1H, m)(, 3.15 (3H, s), 2.06 (2H, m), 1.79 (3H, s),1.80-1.96 (2H, m), 0.92 (3H, t).

EXAMPLE 1743-Cyclobutyloxy-5,5-dimethyl-4-(4-methylsulfonylphenyl-5H-furan-2-one

Following the procedure described for Example 14, the title compound wasobtained using cyclobutyloxyacetic acid. M.P. 111°-112° C.; Ms (Cl, CH₄)m/z 337 (M+H)⁺ ; anal, calcd for C₁₇ H₂₀ O₅ S: C, 60.70; H, 5.99; S,9.53; found: C, 60.39; H, 6.05; S, 9.60.

EXAMPLE 1753-(1-Indanyloxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 14, the title compound wasobtained using 1-indanyloxyacetic acid. M.p. 128°-129° C.; MS (Cl, CH₄)m/z 398 (M+H)⁺ ; and anal. calcd. for C₂₂ H₂₂ O₅ S: C, 66.31; H, 5.56;S, 8.05; found: C, 66.27; H, 5.47; 5, 8.34.

EXAMPLE 1763-(2-Indanyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one

Following the procedure described for Example 14, the title compound wasobtained using 2-indanyloxyacetic acid. M.p. 142°-143° C.; Ms (Cl, CH₄)m/z 3.99 (M+H)⁺ ; anal. calcd. for C₂₂ H₂₂ O₅ S: C, 66.31; H, 5.56;found: C, 66.50; H, 5.64.

EXAMPLE 1773-Cyclopentyloxy-5,5-dimethyl-4-(4-methylsulfonylphenyl)5H-furan-2-one

Following the procedure described for Example 109 the title compound wasprepared from cyclopentyl bromide. M.P.: 121°-122° C.

¹ H NMR (CD₃ COCD₃) δ 1.55-1.85 (8H, m), 1.65 (6H, s), 3.15 (3H, s),5.43 (1H, m), 7.98-8.07 (4H, m).

EXAMPLE 1783-(3,3-Dimethylcyclopentyloxy)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-5H-furan-2-one

Step 1: 3,3-Dimethylcyclopentanol

To a solution of 4,4-Dimethyl-2-cyclopenten-1-one (1.65 g, 15 mmol) inEtOAc (50 mL) was added palladium on activated carbon (270 mg). Theresulting suspension was vigorously stirred under an hydrogen atmospherefor 22 hours. The reaction was diluted with CH₂ Cl₂ (150 mL) andfiltered on a pad of silica gel washed with EtOAc. The solvents wereremoved by distillation under atmospheric pressure using a 15 cm Vigreuxcolumn. The distillation residue was dissolved in MeOH (50 mL) cooled to0° C. and sodium borohydride (304 mg, 8 mmol) was added and to reactionmixture was stirred at r.t. for 24 h. The reaction was diluted with NH₄OAc eq. 25% w/r and extract with EtOAc. The organic layer was separated,dried over MgSO₄ and concentrated. Purification by silica gelchromatography (50% Et2O/pentane) provided 1.14 g of the title compoundas a colorless liquid.

¹ H NMR (CD₃ COCD₃) δ 0.94 (3H, s) 1.07 (3H, s). 1.25-1.4 (2H, m),1.55-1.63 (2H, m), 1.67 (1H, dd), 1.85-1.95 (1H, m), 3.42 (1H, d), 4.27(1H, m).

Step 2: 3-Iodo-1,1-dimethylcyclopentane

To a 0° C. solution of 3,3-Dimethylcyclopentanol (Step 1) (1.14 g, 10mmol) and triethylamine (2.0 mL, 14.3 mmol) in dichloromethane was addeddropwise methanesulfonyl chloride (1.0 mL, 12.9 mmol). The reaction wasallowed to proceed for 30 min. at 0° C., then it was diluted with waterand extracted twice with CH₂ Cl₂. The combined organic layers were driedover MgSO4 and concentrated in vacuo. The resulting residue wasdissolved in acetone (50 mL), cooled to 0° C. and lithium iodide (6.68,50 mmol) was added). The resulting suspension was stirred at r.t. for 20hours. Most of the solvent was removed in vacuo, the residue was takenin EtOAc and washed twice with water. The organic layer was dried overMgSO₄ and concentrated. This crude product was purified by flashchromatography eluted with 40 Et₂ O/pentane to give the title compoundas a colorless oil.

¹ H NMR (CD₃ COCD₃) δ 0.98 (3H, s), 1.14 (3H, s), 1.38-1.46 (1H, m),1.57-1.64 (1H, m), 1.93 (1H, dd), 2.06-2.16 (2H, m), 2.29 (1H, m), 4.38(1H, quintet)

Step 3:

Following the procedure described for Example 109, the title compoundwas prepared from 3-iodo-1,1-dimethylcyclopentanol (Step 2).

M.P.: 99°-100° C.

¹ H NMR (CD₃ COCD₃) δ 0.93 (3H, s), 0.99 (3H, s), 1.32-1.40 (1H, m),1.48-1.62 (2H, m), 1.65 (6H, s), 1.74 (1H, dd), 1.78-1.88 (1H, m),1.93-2.02 (1H, m), 3.17 (3H, s), 5.90 (1H, m), 8.02 (4H, dm).

EXAMPLE 1793-Isopropoxy-5-methyl-4-(4-methylsulfonylphenyl)-5-propyl-5H-furan-2-one

Following the procedure described for Example 171, the title compoundwas prepared from isopropoxyphenyl acetic acid. M.P.: 95°-96° C.

¹ H NMR (CD₃ COCD₃) δ 0.88 (3H, t), 1.12-1.32 (2H, m), 1.28 (6H, 2d),1.67 (3H, s), 2.00 (2H, m), 3.17 (3H, s), 5.22 (1H, heptet), 8.04 (4H,s).

EXAMPLE 1803-(2-Methoxy-5-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Step 1: 5-Hydroxy-2-methoxypyridine

To 6M aqueous HCl(20 mL) at 00 C. was added5-amino-2-methoxypyridine(3.1 g, 25 mmol), stirred for 10 min and asolution of 4M aqueous NaNO2(7 mL, 28 mmol) was added dropwise over aperiod of 10 min. After further stirring for 30 min, 60% HPF6(2 mL) wasadded and precipitate formed immediately. The mixture was stirred for 15min, H2O(50 mL) was added. The precipitate was collected, washed withH2O(3×) and dried under vacuum to give the corresponding diazonium saltas brown powders(6.5 g, 92%).

The above diazonium salt in acetic anhydride(25 mL) was heated at100-1100 C. for 1 h. Solvent was evaporated in vacuo. The residue wasdiluted with H2O and extracted with Et2O. Solid residue was filtered andthe ethereal layer was separated, washed with saturated aq. NaHCO3brine, dried(anhydrous MgSO4) and concentrated to provide the5-acetoxy-2-methoxypyridine as a brown oil(600 mg).

¹ H NMR(CD3COCD3) δ 2.26(3H, s), 3.85(3H, s), 6.78(1H, d), 7.48(1H, dd),7.92(1H, d).

To a solution of the 5-acetoxy-2-methoxypyridine(600 mg, 3.59 mmol) inMeOH(10 mL) was added 1M aq. NaOH(10 mL, 10 mmol). After stirring atr.t. for 30 min, volatile solvent was removed in vacuo, acidified withHOAc and extracted with CHCl3(3×). The combined CHCl3 extracts werewashed with H2O, dried(anhydrous MgSO₄) and evaporated to give the titlecompoud as a brown oil(240 mg, solidified on standing).

¹ H NMR(CD3COCD3) δ 3.78(3H, s), 6.60(1H, d), 7.20(1H, dd), 7.70(1 H,d), 8.20(1 H, br s).

Step 2:3-(2-Methoxy-5-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 5-hydroxy-2-methoxypyridine.

¹ H NMR(CD₃ COCD₃) δ 1.75(6H, s), 3.16(3H, s), 3.85(3H, s), 6.66(1H, d),7.47(1H, dd), 7.90(2H, d), 7.95(1H, d), 8.04(2H, d).

EXAMPLE 1813-(5-Methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Step 1: 2-Hydroxy-5-methylpyridine

Following the procedure described for Example 48, step 1, the titlecompound was prepared from 2-amino-5-picoline.

¹ H NMR(CD₃ COCD₃) δ 2.05(3H, s), 6.36(1H, d), 7.24(1H, d), 7.35(1H,dd).

Step 2:3-(5-Methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 2-hydroxy-5-methylpyridine.

¹ H NMR(CD₃ COCD₃) δ 1.75(6H, s), 2.28, 3.16(3H, s), 6.98(1H, d),7.68(1H, dd), 7.90(2H, d), 7.96(1H, d), 8.04(2H, d).

EXAMPLE 184(5RS)-3-(3,4-Difluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one

Step 1:2(RS)-2-Methyl-1-(4-(methylthio)phenyl)-4,4,4-trifluoro-1-butanone

Following the procedure described for example 1, step 1, the titlecompound was prepared from 2(RS)-2-methyl-4,4,4-trifluoro-butrylchloride(GB 2238790-A) and thioanisole.

¹ H NMR(CD3COCD3) δ 1.22(3H, d), 2.30(1H, m), 2.52(3H, s), 2.82(1H, m),3.88(1H, m), 7.35(2H, d), 7.92(2H, d).

Step 2:2-(RS)-2-Hydroxy-2-methyl-1-(4-(methylthio)phenyl)-4,4,4-trifluoro-1-butanone

To2-(RS)-2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)-4,4,4-trifluoro-1-butanone(12g, 45.8 mmol ) and triethyl phosphite(16 mL) in DMF(250 mL) at -10° C.was added 1M t-BuOK(46 mL, 46 mmol) in t-BuOH and air was bubbledthrough the mixture for 3 h. After quenching with 2.5M aq. HOAc(20 mL),the mixture was diluted with H₂ O, extracted with Et₂ O. The etheralextract was washed with H₂ O(2×), 0.5M aq. NaOH, dried(anhydrous MgSO₄)and concentrated. Chromatography over silica gel and elution withhexanes:EtOAc(4:1) gave the title compound as a yellow oil(6.0 g, ˜90%pure).

¹ H NMR(CD₃ COCD₃) δ 1.62(3H, s), 2.54(3H, s), 2.70-3.20(2H, m),7.32(2H, d), 8.15(2H, d).

Step 3:2-(RS)-2-Hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)-4,4,4-trifluoro-1-butanone

To a solution of2-(RS)-2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)-4,4,4-trifluoro-1-butanone(6.0g, 21.6 mmol) in CH₃ Cl(200 mL) was added mCPBA(12 g, Aldrich 27,303-1,57-86%) at 0° C. The mixture was slowly warmed to r.t. over a period of1 h, washed with 1M aq. NaOH(2×), brine, dried(anhydrous MgSO⁴) andconcentrated. Chromatography over silica gel and elution withhexanes:EtOAc(2:1) provided the title compound(4.0 g, 60%).

¹ H NMR(CD³ COCD³) δ 1.66(3H, s), 2.70-3.20(2H, m), 3.18(3H, s),5.35(1H, s), 8.04(2H, d), 8.30(2H, d).

Step 4:(5RS)-3-(3,4-Difluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one

Following the procedure described for example 1, step 4, the titlecompound was prepared from 3,4-difluorophenoxyacetic acid and2-(RS)-2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)-4,4,4-trifluoro-1-butanone.NMR of the title compound is the same as Example 168.

EXAMPLE 1853-(3-Chloro-4-methoxyphenoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Step 1: 3-Chloro-4-methoxyphenoxyacetic acid

To a mixture of hydroquinone(24 g, 0.22 mol) and ethyl bromoacetate(24mL, 0.22 mol) in DMF(300 mL) was added 10M aq. NaOH(22 mL, 0.22 mol).The mixture was stirred at 0° C. for 1 h, diluted with H2O, acidifiedwith 6M aq. HCl and extracted with EtOAc. The EtOAc extract wasdried(anhydrous MgSO₄) and concentrated in vacuo. The residue wasswished with Et2O to give ethyl 4-hydroxyphenoxyacetate (5.8 g) as awhite powder.

Ethyl 4-hydroxyphenoxyacetate(1.58, 7.6 mmol) was reacted with SO₂ Cl₂(1.5 mL) to give ethyl 3-chloro-4-hydroxyphenoxyacetate (700 mg, ˜80%pure) as a white powder. To a solution of ethyl3-chloro-4-hydroxyphenoxyacetate(700 mg, 3.0 mmol) and MeI(0.280 mL, 4.5mmol) in DMF(5 mL) at 0° C. was added 10M aq.NaOH(0.320 mL, 3.2 mmol).The mixture was stirred at r.t. for 12 h, then diluted with H₂ O andextracted with EtOAc to give ethyl 3-chloro-4-methoxyphenoxyacetate (700mg).

The above ethyl 3-chloro-4-methoxyphenoxyacetate (700 mg) was hydrolysedwith 1M aq. NaOH in THF-MeOH (30 mL, 2:1) to provide the title compoundas a white powder.

¹ H NMR(CD3COCD3) δ 3.84(3H, s), 4.70(2H, s), 6.85-7.10(3H, m).

Step 2:3-(3-Chloro-4-methoxyphenoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for example 1, step 4, the titlecompound was prepared from 3-chloro-4-methoxyphenoxyacetic acid and2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl)propan-1-one (example 1,step 3).

¹ H NMR(CD3COCD3) δ 1.75(6H, s), 3.14(3H, s), 3.84(3H, s), 6.95-7.20(3H,m), 7.86(2H, d), 8.00(2H, d).

EXAMPLE 186(5R)-3-(3-Chloro-4-methoxyphenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)-5H-furan-2-one

Following the procedure described for Example 1, step 4, the titlecompound was prepared from 3-chloro-4-methoxyphenoxyacetic acid and(2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl-butan-1-one (Example117, Step 3).

¹ H NMR(CD3COCD3) δ 0.94(3H, t), 1.76(3H, s), 2.10(2H, q), 3.15(3H, s),3.85(3H, s), 6.95-7.20(3H, m), 7.90(2H, d), 8.00(2H, d).

EXAMPLE 188(5R)-3-(4-Chlorophenoxy)-5-(2,2,2-trifluoroethyl)-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 1, Step 4, the titlecompound was prepared from 4-Chlorophenoxyacetic acid and(2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl-4,4,4-trifluoro-butan-1-one(Example 130, Step 2).

¹ H NMR(CD₃ COCD₃) δ 1.95 (3H, s), 3.15 (3H, s), 3.25 (2H, m), 7.12 (2H,d), 7.36 (2H, d), 8.02 (4H, m).

Analysis calculated for C₂₀ H₁₆ ClF₃ O₅ S: C, 52.13; H, 3.50. Found: C,52.27; H, 3.63.

EXAMPLE 189(5R)-3-(4-Bromophenoxy)-5-(2,2,2-trifluoroethyl)-5-methyl-4-(4-methylsulfonyl)-5H-furan-2-one

Following the procedure described for Example 1, Step 4, the titlecompound was prepared from 4-bromophenoxyacetic acid and(2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl-4,4,4-trifluorobutan-1-one(Example 130, Step 2).

¹ H NMR(CD₃ COCD₃) δ 1.94 (3H, s), 3.15 (3H, s), 3.25 (2H, m), 7.07 (2H,d), 7.50 (2H, d), 8.02 (4H, m).

EXAMPLE 1955-Cyclopropylmethyl-3-(3,4-difluorophenoxy)-5-methyl-(4-methylsulfonyl)phenyl-5H-furan-2-one

Step 1: 2-Cyclopropylmethyl-2-methyl-1-(4-thiomethyl)phenyl-propan-1-one

To a cold (-78° C.) solution of 1-(4-thiomethyl)phenyl-propan-1-one (900mg, 5 mmol) in dry THF (15 mL) was added a solution of KHMDS (5.5 mmol,11 mL). The mixture was warmed to r.t. for 5 min and then cooled to 0°C. Bromomethylcyclopropane (810 mg, 6 mmol) was added. The mixture waswarmed to r.t. and stirred for 20 h. Aqueous NH₄ Cl solution was added.The mixture was extracted with EtOAc and the concentrated crude extractwas purified by chromatography on silica gel (eluted with 20%EtOAc/hexane) to give 435 mg (37%) of the title compound.

Step 2:2-Cyclopropylmethyl-2-methyl-1-(4-methylsulfonyl)phenyl-propan-1-one

To a solution of the product of step 1 (435 mg, 1.87 mmol) in a mixtureof CH₂ ClCH₂ Cl (10 mL) and methanol (10 mL) was added MMPP (2.3 g 3.7mmol) in 2 portions. The mixture was stirred at r.t. for 6 h. H₂ O wasadded and the product was extracted with EtOAc. The extracts were washedwith H₂ O and brine, dried and concentrated to an oil. The crude oil waspurified by chromatography on silica gel (eluted with 30% EtOAc/hexane)to give 363 mg (83%) of the title compound.

Step 3:-Cyclopropylmethyl-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenyl-propan-1-one

To a mixture of the product of step 2 (310 mg, 1.16 mmol), CCl₄ (268 mg,1.74 mmol), Aliquat 336® (75 mg, 0.185 mmol) and toluene (293 mg, 3.19mmol) was added powered NaOH (102 mg, 2055 mmol) in portions. AqueousNH₄ Cl solution was added. The mixture was neutralized with 1N HCl andextracted with EtOAc and the concentrated crude extract was purified bychromatography on silica gel (eluted with 30% EtOAc/hexane) to give 124mg (38%) of the title compound.

Step 4:5-Cyclopropylmethyl-3-(3,4-difluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furano2-one

Following the procedure described for Example 117, the title compoundwas prepared from the product of step 3 and 3,4-difluorophenoxyaceticacid.

¹ H NMR(CD₃ COCD₃) δ-0.01 (1H, m), 0.19 (1H, m), 0.42 (1H, m), 0.51 (1H,m), 0.71 (1H, m), 1.82 (3H, s), 1.87 (1H, dd), 2.26 (1H, dd), 3.15 (3H,s), 6.95 (1H, m), 7.14 (1H, m), 7.29 (1H, q), 8.05 (4H, q).

EXAMPLE 196(5R)-3-(3-Fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 3-fluorophenol and(2R)-2-chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenyl-butan-1-one,prepared as in Example 162.

¹ H NMR(CD₃ COCD₃) δ 0.93 (3H, t), 1.79 (3H, s), 2.13 (2H, q), 3.15 (3H,s), 6.89 (3H, m), 7.46 (1H, q), 7.93 (2H, d), 8.05 (2H, d).

EXAMPLE 197(5R)-3-(4-Chloro-3-fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 4-chloro-3-fluorophenoxyacetic acid and(2R)-2-chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenyl-butan-1-one.

¹ H NMR(CD₃ COCD₃) δ 0.94 (3H, t), 1.80 (3H, s), 2.13 (2H, q), 3.15 (3H,s), 6.95 (1H, m), 7.10 (1H, m), 7.48 (1H, t), 7.94 (2H, d), 8.04 (2H,d).

EXAMPLE 198(5R)-3-(3-Phenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from phenol and(2R)-2-chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenylbutan-1-one,prepared as in Example 162.

¹ H NMR(CD₃ COCD₃) δ 0.94 (3H, t), 1.78 (3H, s), 2.15 (2H, q), 3.14 (3H,s), 7.09 (3H, m), 7.33 (2H, m), 7.93 (2H, d), 8.01 (2H, d).

Analysis calculated for C₂₀ H₂₀ O₅ S: C, 64.50; H, 5.41. Found: C,63.94; H, 5.48.

EXAMPLE 199(5R)-3-(4-Chloro-3-methylphenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)-5H-furan-2-one

Following the procedure described for Example 25, the title compound wasprepared from 4-chloro-3-methylphenol and(2R)-2-chloroacetoxy-2-methyl-1-(4-methylsulfonyl)phenyl-butan-1-one,prepared as in Example 162.

¹ H NMR(CD₃ COCD₃) δ 0.93 (3H, t), 1.78 (3H, s), 2.12 (2H, q), 2.30 (3H,s), 3.15 (3H, s), 6.91 (1H, dd), 7.04 (1H, d), 7.30 (1H, d), 7.92 (2H,d), 8.02 (2H, d).

Analysis calculated for C₂₁ H₂₁ ClO₅ S: C, 59.93; H, 5.03. Found: C,59.59; H, 5.02.

EXAMPLE 2003-(4-Chloro-3-methylphenoxy)-5-5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Following the procedure described for Example 108, the title compoundwas prepared from 4-chloro-3-methylphenoxyacetic acid and2-chloroacetoxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one.

¹ H NMR(CD₃ COCD₃) δ 1.76 (6H, s), 2.79 (3H, s), 3.15 (3H, s), 6.92 (1H,dd), 7.06 (1H, d), 7.28 (1H, d), 7.92 (2H, d), 8.02 (2H, d).

Analysis calculated for C₂₁ H₁₉ ClO₅ S: C, 59.04; H, 4.71. Found: C,59.18; H, 4.78.

EXAMPLE 201(5R)-3-(5-bromo-2-pyridyloxy)-4-(4-methylsulfonylphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one

Step 1:(5R)-4-methyl-4-(2,2,2-trifluoroethyl)-5-(4-methylsulfonylphenyl)-3,6-dioxabicyclo3.1.0!hexan-2-one

To a 0° C. solution of the chloroacetate(1.16 g, 3 mmol) from step 3,Example 130, in acetonitrile(15 mL) was added DBU(0.491 mL, 3.3 mmol)and the mixture was warmed up to 25° C. After 2 hours, the mixture waspoured on icy 1N HCl and ethyl acetate; the organic layer was separatedand the aquous further extracted once with ethyl acetate. The combinedorganic layers were washed with brine, dried with MgSO₄ and the solventswere removed in vacuo to yield the essentially pure title compound(0.930g).

¹ H NMR (CD₃ COCD₃) δ 1.60-1.70(3H, 2s), 2.50-3.05(2H, m), 3.13(3H, s),4.40-4.30(1H, 2s), 7.95-8.05(4H, 2d).

Step 2:(5R)-3-(5-bromo-2-pyridyloxy)-4-(4-methylsulfonylphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one

To a 0° C. mixture of the epoxide(0.930 g) from step 1 indimethylformamide(3 mL) and isopropanol(12 mL) was added the potassiumsalt of 5-bromo-2-hydroxypyridine, prepared from5-bromo-2-hydroxypyridine and one equivalent of 8N KOH followed byevaporation to dryness with toluene and high vacuum drying, (0.742 g,3.5 mmol) and the mixture was warmed up slowly to reflux for 16 hrs. Itwas then cooled to room temperature and poured on icy dilute ammoniumchloride and ethyl acetate; the organic layer was separated and theaquous further extracted ounce with ethyl acetate. The combined organiclayers were washed with brine, dried with MgSO₄ and the solvents wereremoved in vacuo to yield after purification on silica gel(10%acetone/toluene) the title compound (0.380 g).

¹ H NMR (CD₃ COCD₃) δ 1.90(3H,s), 3.15(3H,s), 3.15-3.30(2H,AB),7.15(1H,d), 7.95-8.10(5H,m), 8.25(1H,d).

EXAMPLE 202(5R)-3-(5-bromo-2-pyridyloxy)-4-(4-methylsulfonylphenyl)-5-ethyl-5-methyl-5H-furan-2-one

Step 1:

To a 25° C. mixture of (2R)-chloroacetic acid2-methyl-1-(4-(methylsulfonyl)phenyl)butan-1-one ester (0.896 g, 2.7mmol prepared as in Example 162) and 5-bromo-2-hydroxypyridine (0.560 g,3.2 mmol) in acetonitrile(20 mL) was added DBU(1.5 mL) and the mixturewas warmed up to 70°-80° C. for 2 hrs. The volatiles were then removedin vacuo and the mixture purified on silica gel(10% acetone/toluene) toyield the title compound(0.587 g)

¹ H NMR (CD₃ COCD₃) δ 0.90-1.0(3H,t), 1.75(3H,s), 2.00-2.15(2H,m),3.15(3H,s) 7.10-7.15(1H,d), 7.85-8.05(4H,2d), 8.20-8.30(1H,d).

EXAMPLE 2033-(5-Chloro-6-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Step 1:3-(5-Nitro-6-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)-5H-furan-2-one

A suspension made of the alcohol(2.82 g, 10 mmol) from step 1 Example109, 3-nitro-6-chloro-2-picoline C.A.70:114970s! (2.06 g, 12 mmol) and10N NaOH(1.1 mL) in DMF(35 mL) was warmed up to to 105° C. for 8 hrs. Itwas then cooled to room temperature and poured on icy H₂ O and ethylacetate. The pH was adjusted to c.a. 8 then the organic layer wasseparated and the aqueous further extracted ounce with ethyl acetate.The combined organic layers were washed with brine, dried with MgSO₄ andthe solvents were removed in vacuo to yield after purification on silicagel(10% acetone/toluene) the title compound (4.180 g).

¹ H NMR (CD₃ COCD₃) δ 1.75(6H,s), 2.70(3H,s), 3.15(3H,s),7.15-7.20(1H,d), 7.85-8.05(4H,2d), 8.45-8.55(1H,d).

Step 2:3-(5-Amino-6-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

A mixture of the compound from the previous step(3.19 g, 7.6 mmol),ammonium chloride(0.250 g) and iron powder(3 g) in ethanol(50 mL) and H₂O(20 mL) was warmed up to reflux for 1.5 hrs after what it was filteredquickly, while hot, over celite. To the filtrate was added water(250 mL)and ethyl acetate. The organic layer was separated and the aquousfurther extracted ounce with ethyl acetate. The combined organic layerswere washed with brine, dried with MgSO₄ and the solvents were removedin vacuo to yield after purification by swish in diethyl ether the titlecompound (3.0 g).

¹ H NMR (CD₃ SOCD₃) δ 1.75(6H,s), 2.10(3H,s), 3.25(3H,s), 4.75-4.85(2H,bs), 6.65-6.70(1H,d), 7.00-7.05(1H,d), 7.80-8.00(4H,2d).

Step 3:3-(5-chloro-6-methyl-2-pyridyloxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one

Sodium nitrite(0.152 g, 2.2 mmol) in H₂ O(1 mL) was added dropwise to a0° C. suspension of the compound(0.776 g) from the previous step in 6NHCl(4 mL) and the mixture was stirred at 0° C. for 0.5 hr. It was thentransfered dropwise into a CUCl(0.396 g, 4 mmol) solution in 12N HCl(3mL). The reaction mixture was warmed up to 80° C. for c.a. 10 min. thencooled to 25° C. The mixture was poured on icy H₂ O and the pH adjustedto c.a. 4-5 then ethyl acetate was added. The organic layer wasseparated and the aquous further extracted ounce with ethyl acetate. Thecombined organic layers were washed with brine, dried with MgSO₄ and thesolvents were removed in vacuo to yield after purification by swish indiethyl ether the title compound (0.310 g).

¹ H NMR (CD₃ COCD₃) δ 1.75(6H,s), 2.40(3H,s), 3.15(3H,s),6.90-7.00(1H,d), 7.75-7.85(1H,d), 7.85-8.05 (4H,2d).

EXAMPLE 2073-(1-Cyclopropylethoxy)-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one

Step 1: 3-Diazo-2,4-(3H, 5H)-furandione

To tetronic acid (5.00 g, 49.9 mmol) in CH2Cl2 (250 mL) at 0° C. wereadded Et₃ N (8.3 mL, 59.6 mmol) and tosyl azide (7.37 g, 37.4 mmol).After a period of 2 h at r.t., the reaction mixture was partitionedbetween NH4OAc (25%) and CH2Cl2. The organic phase was dried overNa2SO4, filtered and evaporated under reduced pressure. The resultingmixture was purified by flash chromatography (20% to 35% EtOAc inHexane) to provide 1.4 g of the title compound as a white solid.

Step 2: 3-(1-cyclopropylethoxy)-4-hydroxy-2(5H)-furanone

To the mixture of 3-diazo-2,4-(3H,5H)-furandione (300 mg, 2.38 mmol;Example 207, Step 1) and α-methylcyclopropanemethanol (2.0 mL) was addedrhodium acetate (30 mg). The mixture was heated at 130° C. for a periodof 18 h. The excess of alcohol was evaporated under reduced pressure andthe resulting crude mixture was purified by flash chromatography (10% to20% MeOH in CH2Cl2) to provide 50 mg of the title compound.

Step 3: 3-(1-cyclopropylethoxy)-4-(4-methylthio)phenyl)-5H-furan-2-one

To a mixture of 3-(1-cyclopropylethoxy)-4-hydroxy-2-(5H)furanone (50 mg,0.27 mmol; Example 207, Step 2) and diisopropylethylamine (0.066 mL,0.38 mmol) in CH2Cl2 (2.0 mL) at -20° C. was addedtrifluoromethanesulfonic anhydride (0.060 mL, 0.36 mmol). After a periodof 5 min. at -20° C., the reaction mixture was brought to 0° C. then tor.t. The reaction mixture was partitioned between NH4OAc (25%) andCH2Cl2. The organic phase was dried over Na2SO4, filtered and evaporatedunder reduced pressure. The title compound was purified by flashchromatography to provide 30 mg of material.

Step 4:3-(1-cyclopropylethoxy)-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one

To a mixture of3-(1-cyclopropylethoxy)-4-(4-methylthio)phenyl)-5H-furan-2-one (30 mg,0.10 mmol; Example 207, Step 3) in CH2Cl2 ((1.0 mL) MeOH (3.0 mL) wereadded an excess of OXONE® (150 mg). After the TLC showed completion, thereaction mixture was extracted with EtOAc. The organic phase was driedover Na2SO4 filtered and evaporated under reduced pressure. The titlecompound was purified by flash chromatography to provide 6 mg ofmaterial.

¹ H NMR (CD3COCD3) δ 0.20-0.60 (4H,m), 1.10 (1H,m), 1.45 (3H,d), 3.20(3H,s), 4.50 (1H,m), 5.30 (2H, s), 8.10 (4H, m).

EXAMPLE 2083-(1-Cyclopropylmethoxy)-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one

The title compound was prepared as described in Example 207.

¹ H NMR (CD3COCD3) δ 0.40-0.65 (4H,m), 1.30 (1H,m), 3.20 (3H,s), 4.30(2H, d), 5.30 (2H, s), 8.05 (4H, m).

PREPARATION OF THE PRECURSOR FOR EXAMPLE 403-(4-(Methylsulfonyl)phenyl)-2-(3-pyridinyl)-2-cyclopenten-1-one

Step 1: 2-Bromo-2-cyclopenten-1-one

To a 0° C. solution of 2-cyclopenten-1-one (125 g, 1.52 mol) in CCl₄(1.2 L) in a three-neck flask equipped with an overhead stirrer wasadded a solution of bromine (269 g, 1.68 mol) in CCl₄ (400 mL) dropwiseover 4 h, maintaining an internal temperature <2° C. A solution of Et₃ N(310 mL, 2.22 mol) in CCl₄ (200 mL) was then added dropwise over 1.5 h,maintaining an internal temperature <10° C. The resulting suspension waswarmed to r.t. for 1 h, then cooled to 0° C. and filtered. The filtratewas washed with two 700 mL portions of 3M HCl and 500 mL of brine, thenfiltered through cotton. Concentration provided 228 g of an orange oilwhich was crystalized from 150 mL of 2:1 hexane:ether to provide 191 gof the title compound.

¹ H NMR (CD₃ COCD₃) δ 7.94 (1H, t), 2.72 (2H, m), 2.46 (2H, m).

Step 2: 2-Bromo-3-(4-(methylthio)phenyl)-2-cyclopenten-1-one

To a -78° C. solution of 4-bromothioanisole (35.1 g, 173 mmol) in THF(500 mL) was added nBuLi (1.6M in hexanes, 107.5 mL, 172 mmol). Thesolution was stirred for 45 min, then a solution of2-bromo-2-cyclopenten-1-one (25.4 g, 158 mmol) in THF (150 mL) was addedand the mixture was allowed to warm to 0° C. and was quenched withsaturated aqueous NH₄ Cl. The majority of the solvent was removed invacuo and the residue was suspended in water and extracted with twoportions of EtOAc. The organic layers were washed with brine, dried overMgSO₄, faltered and concentrated. This material was dissolved in DMF(300 mL), cooled to 0° C. and treated with PDC (72.4 g, 192 mmol). Theresulting mixture was warmed to r.t. and stirred for 2 h, then pouredinto H₂ O (1.2 L) and extracted with two 500 mL portions of EtOAc. Theorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated to give the title compound as a light brown solid which wasused directly in the next step.

Step 3: 2-Bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one

To a 0° C. solution of2-bromo-3-(4-(thiocychyl)phenyl)-2-cyclopenten-1-one in 2:1 CH₂ Cl₂/MeOH (500 mL) was added MMPP (100 g). The mixture was stirred at r.t.overnight, then concentrated and partitioned between saturated NaHCO₃,1M Na₂ S₂ O₃ and CH₂ Cl₂. The aqueous layer was extracted with CH₂ Cl₂,and the combined organics were washed with brine, filtered throughcotton and evaporated. The resulting solid was swished in CH₂ Cl₂ /Et₂ Oto provide 23 g of the title compound.

¹ H NMR (CD₃ COCD₃) δ 8.12 (4H, m), 3.22 (2H, m), 3.20 (3H, s), 2.69(2H, m).

Step 4: Lithium 3-pyridinyltrimethyl boronate

To a -88° C. solution of 3-bromopyridine (10.1 mL, 104.8 mmol) in Et₂ O(450 mL) was added a 1.6M hexane solution of n-BuLi (66 mL, 105.6 mmol).The reaction mixture was warmed to -78° C. for 1 h to give a thickyellow slurry. Triisopropyl borate (26 mL, 112.7 mmol) was then added togive a slight exotherm (-78° C. to -63° C.) and a clear solution. Themixture was stirred at -78° C. for 15 min, then warmed to r.t. andconcentrated to dryness. The residue was dissolved in MeOH andconcentrated three times to give 27.2 g of pyridin-3-yl-trimethyllithium boronate. This material was used in the next step withoutfurther purification.

¹ H NMR (CD₃ OD, 400 MHz) δ 7.15 (1H, m), 7.85 (1H, m), 8.15 (1H, m),8.50 (1H, m)

Step 5: 3-(4-(Methylsulfonyl)phenyl)-2-(3-pyridinyl)-2-cyclopenten-1-one

To a mixture of 2-bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one(3.37 g, 10.7 mmol), lithium 3-pyridinyltrimethyl boronate (3.43 g, 18.2mmol), Pd₂ (dba)₃ (0.196 g, 0.214 mmol), and PPh₃ (0.224 g, 0.855 mmol)was added toluene (75 mL), n-propanol (25 mL), and H₂ O (25 mL). Themixture was degassed and stirred under N₂ for 15 min then heated toreflux. After 4 h, the reaction mixture was cooled to r.t., diluted with100 mL of CH₂ Cl₂ and washed with H₂ O. The aqueous layer was separatedand washed 3 times with 100 mL of CH₂ Cl₂. The organic layers werecombined, washed with brine and filtered through cotton. The filtratewas concentrated to dryness and the residue was purified by flashchromatography (100% EtOAc) followed by swishing in a mixture of CH₂ Cl₂and Et₂ O to provide 2.6 g of the title compound.

¹ H NMR (CDCl₃) δ 8.55 (1H, m), 8.34 (1H, m), 7.40 (2H, m), 7.65 (1H,m), 7.49 (2H, m), 7.33 (1H, m), 3.12 (2H, m), 3.05 (3H, s), 2.80 (2H,m).

What is claimed is:
 1. A compound of Formula I ##STR65## or apharmaceutically acceptable salt thereof wherein: R¹ is selected fromthe group consisting of(a) S(O)₂ CH₃, (b) S(O)₂ NHR⁸, (c) S(O)₂NHC(O)CF₃, (d) S(O)(NH)NH₂, (e) S(O)(NH)NHC(O)CF₃, (f) P(O)(CH₃)NH₂, (g)P(O)(CH₃)₂, and (h) C(S)NH₂ ; R² is selected from the group consistingof(a) NR¹⁰ R¹¹, (b) SR¹¹, (c) OR¹¹, (d) R¹¹, (e) C1-10alkenyl, (f)C1-10alkynyl, (g) unsubstituted, mono-, di-, tri- or tetra-substitutedC₃ -C₁₀ cycloalkenyl wherein the substituents are independently selectedfrom the group consisting of(1) halo, (2) C₁₋₆ alkoxy, (3) C₁₋₆alkylthio, (4) CN, (5) CF₃, (6) C₁₋₁₀ alkyl, (7) N₃, (8) --CO₂ H, (9)--CO₂ --C₁₋₁₀ alkyl, (10) --C(R¹²)(R¹³)--OH, (11) --C(R¹²)(R¹³)--O--C₁₋₄alkyl, (12) --C₁₋₁₀ alkyl-CO₂ --R¹² ; (13) benzyloxy, (14) --O--(C₁₋₁₀alkyl)-CO₂ R¹², and (15) --O--(C₁₋₁₀ alkyl)-NR¹² R¹³ ; (h) a mono-, di-,tri- or tetra-substituted heterocycloalkyl group of 5, 6 or 7 members ora benzoheterocycle wherein said heterocycloalkyl or benzoheterocyclecontains 1 or 2 heteroatoms selected from O, S, or N and optionallycontains a carbonyl group or a sulfonyl group, and wherein saidsubstituents are independently selected from the group consisting of(1)halo, (2) C₁₋₁₀ alkyl, (3) C₁₋₁₀ alkoxy, (4) C₁₋₁₀ alkylthio, (5) CN,(6) CF₃, (7) N₃, (8) --C(R¹²)(R¹³)--OH, and (9) --C(R¹²)(R¹³)--O--C₁₋₁₀alkyl; (i) styryl or mono or di-substituted styryl wherein thesubstituent are independently selected from the group consisting of(1)halo, (2) C₁₋₆ alkoxy, (3) C₁₋₆ alkylthio, (4) CN, (5) CF₃, (6) C₁₋₁₀alkyl, (7) N₃, (8) --CO₂ H, (9) --CO₂ --C₁₋₁₀ alkyl, (10)--C(R¹²)(R¹³)--OH, (11) --C(R¹²)(R¹³)--O--C₁₋₄ alkyl, (12) --C₁₋₁₀alkyl-CO₂ --R¹² ; (13) benzyloxy, (14) --O--(C₁₋₁₀ alkyl)-CO₂ R¹², and(15) --O--(C₁₋₁₀ alkyl)-NR¹² R¹³ ; (j) phenylacetylene or mono- ordi-substituted phenylacetylene wherein the substituents areindependently selected from the group consisting of(1) halo, (2) C₁₋₆alkoxy, (3) C₁₋₆ alkylthio, (4) CN, (5) CF₃, (6) C₁₋₁₀ alkyl, (7) N₃,(8) --CO₂ H, (9) --CO₂ --C₁₋₁₀ alkyl, (10) --C(R¹²)(R¹³)--OH, (11)--C(R¹²)(R¹³)--O--C₁₋₄ alkyl, (12) --C₁₋₁₀ alkyl-CO₂ --R¹², (13)benzyloxy, (14) --O--(C₁₋₁₀ alkyl)-CO₂ R¹², (15) --O--(C₁₋₁₀ alkyl)-NR¹²R¹³, (k) C₁₋₁₀ fluoroalkenyl, and (l) mono- or di-substituted bicyclicheteroaryl of 8, 9 or 10 members, containing 2, 3, 4 or 5 heteroatoms,wherein at least one heteroatom resides on each ring of said bicyclicheteroaryl, said heteroatoms independently selected from O, S and N andsaid substituents are independently selected from the group consistingof(1) hydrogen, (2) halo, (3) C₁₋₁₀ alkyl, (4) C₁₋₁₀ alkoxy, (5) C₁₋₆alkylthio, (6) CN, (7) C₁₋₆ fluoroalkyl, including CF₃, (8) N₃, (9)--C(R⁵)(R⁶)--OH, (10) --C(R⁵)(R⁶)--O--C₁₋₁₀ alkyl; R³ is hydrogen, C₁₋₁₀alkyl, CH₂ OR⁸, CN, CH₂ CN, or C₁₋₆ fluoroalkyl, F, CONR⁸ ₂,unsubstituted or mono- or di-substituted phenyl, unsubstituted or monoor di-substituted benzyl, unsubstituted or mono- or di-substitutedheteroaryl, unsubstituted or mono or di-substituted heteroarylmethyl,wherein the substituents are independently selected from the groupconsisting of(1) halo, (2) C₁₋₁₀ alkyl, (3) C₁₋₁₀ alkoxy, (4) C₁₋₁₀alkylthio, (5) CN, (6) CF₃, (7) N₃, (8) --C(R¹²)(R¹³)--OH, and (9)--C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl; R⁴ is(a) hydrogen, (b) C₁₋₁₀ alkyl, (c)C₁₋₁₀ alkoxy, (d) C₁₋₁₀ alkylthio, (e) --OH, (f) --OCOR⁸, (g) --SH, (h)--SCOR⁸, (i) --OCO₂ R⁹, (j) --SCO₂ R⁹, (k) OCONR⁸ ₂, (l) SCONR⁸ ₂ ; (m)C₃₋₁₀ cycloalkoxy, and (n) C₃₋₁₀ cycloalkylthio, or R³ and R⁴ togetherwith the carbon to which they are attached form a monocyclic ring of 3,4, 5, 6, or 7 members which ring optionally contains one or twoheteroatoms selected from O, S or N; R⁵ is selected from the groupconsisting of(a) OR¹⁷, (b) SR¹⁸, (c) NR¹⁷ R¹⁸, (d) NHS(O)₂ R¹⁸, (e)S(O)R¹⁸, (f) S(O)₂ R¹⁸, (g) S(O)₂ NR¹⁷ ₂, (h) OP(O)(OR¹⁶)₂ ; each R⁸ isindependently selected from the group consisting of(a) hydrogen and (b)R⁹ ; each R⁹ is independently selected from the group consisting of(a)C₁₋₁₀ alkyl, (b) --C₁₋₁₀ alkyl-CO₂ H (c) C₁₋₁₀ alkyl-NH₂ (d) phenyl ormono-, di- or tri-substituted phenyl wherein the substituents areindependently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀alkylthio, C₁₋₁₀ alklyCO₂ H, C₁₋₁₀ alkylNH₂, CN, CO₂ H and CF₃, (e)benzyl or mono-, di- or tri-substituted benzyl wherein the substituentsare independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀alkylthio, C₁₋₁₀ alkylCO₂ H, C₁₋₁₀ alkylNH₂, CN, CO₂ H and CF₃, (f)C₃₋₁₀ cycloalkyl, (g) C₁₋₁₀ alkanoyl, and (h) benzoyl or mono-, di-, ortrisubstituted benzoyl wherein the substituents are independentlyselected from halo, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀alkylCO₂ H, --C₁₋₁₀ alkylNH₂, CN, CO₂ H and CF₃, each R¹⁰ isindependently selected from the group consisting of(a) hydrogen and (b)R¹¹ ; R¹¹ is selected from the group consisting of(a) C₁₋₁₀ alkyl, (b)C₃₋₁₀ cycloalkyl, (c) unsubstituted, mono-, di- or tri-substitutedphenyl or naphthyl wherein the substituents are independently selectedfrom the group consisting of(1) halo, (2) C₁₋₁₀ alkoxy, (3) C₁₋₁₀alkylthio, (4) CN, (5) CF₃, (6) C₁₋₁₀ alkyl, (7) N₃, (8) --CO₂ H, (9)--CO₂ --C₁₋₁₀ alkyl, (10) --C(R¹²)(R¹³)--OH, (11) --C(R¹²)(R¹³)--O--C₁₋₄alkyl, (12) --C₁₋₆ alkyl-CO₂ --R¹², (13) benzyloxy, (14) --O--(C₁₋₁₀alkyl)-CO₂ R¹², and (15) --O--(C₁₋₁₀ alkyl)-NR¹² R¹³, (d) unsubstituted,mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is amonocyclic aromatic ring of 5 atoms, said ring having one hetero atomwhich is S, O, or N, and optionally 1, 2, or 3 additional N atoms; orsaid heteroaryl is a monocyclic ring of 6 atoms, said ring having onehetero atom which is N, and optionally 1, 2, or 3 additional N atoms,and wherein said substituents are independently selected from the groupconsisting of(1) halo, (2) C₁₋₁₀ alkyl, (3) C₁₋₁₀ alkoxy, (4) C₁₋₁₀alkylthio, (5) CN, (6) CF₃, (7) N₃, (8) --C(R¹²)(R¹³)--OH, and (9)--C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl; (e) unsubstituted, mono- ordi-substituted benzoheterocycle in which the benzoheterocycle is a 5, 6,or 7-membered ring which contains 1 or 2 heteroatoms independentlyselected from O, S, or N and optionally a carbonyl group or a sulfonylgroup, wherein said substituents are selected from the group consistingof(1) halo, (2) C₁₋₁₀ alkyl, (3) C₁₋₁₀ alkoxy, (4) C₁₋₁₀ alkylthio, (5)CN, (6) CF₃, (7) N₃, (8) --C(R¹²)(R¹³)--OH, and (9)--C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl; (f) unsubstituted, mono- ordi-substituted benzocarbocycle in which the carbocycle is a 5, 6, or7-membered ring which optionally contains a carbonyl group, wherein saidsubstituents are independently selected from the group consisting of(1)halo, (2) C₁₋₁₀ alkyl, (3) C₁₋₁₀ alkoxy, (4) C₁₋₁₀ alkylthio, (5) CN,(6) CF₃, (7) N₃, (8) --C(R¹²)(R¹³)--OH, and (9) --C(R¹²)(R¹³)--O--C₁₋₁₀alkyl; each R¹² or R¹³ is independently selected from the groupconsisting of(a) hydrogen, and (b) C₁₋₁₀ alkyl, or R¹² and R¹³ togetherwith the atom to which they are attached form a saturated monocyclicring of 3, 4, 5, 6 or 7 atoms; each R¹⁶ is independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl and unsubstituted or mono-or disubstituted benzyl, wherein the substituents are selected fromhalo, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio or C₁₋₆ fluoroalkyl;each R¹⁷ is independently selected from the group consisting of(a)hydrogen and (b) R¹⁸ ; and each R¹⁸ is independently selected from thegroup consisting of(a) C₁₋₁₀ alkyl, (b) --C₁₋₁₀ alkyl-CO₂ H (c) C₁₋₁₀alkyl-NH₂ (d) phenyl or mono-, di- or tri-substituted phenyl wherein thesubstituents are independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alklyCO₂ H, C₁₋₁₀ alkylNH₂, CN, CO₂ H andCF₃, (e) benzyl or mono-, di- or tri-substituted benzyl wherein thesubstituents are independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylCO₂ H, C₁₋₁₀ alkylNH₂, CN, CO₂ H andCF₃, (f) C₃₋₁₀ cycloalkyl, (g) H-(oxyethyl)n wherein n is 1 to 6, (h)C₁₋₁₀ alkanoyl, and (i) benzoyl or mono-, di-, or trisubstituted benzoylwherein the substituents are independently selected from halo, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylCO₂ H, --C₁₋₁₀alkylNH₂, CN, CO₂ H and CF₃.
 2. A compound according to claim 1whereinR⁵ is selected from the group consisting of(a) OR¹⁷, (b) SR¹⁸,and (c) NHS(O)₂ R¹⁸.
 3. A compound according to claim 1 wherein:R¹ isselected from the group consisting of(a) S(O)₂ CH₃, (b) S(O)₂ NHR⁸, (c)S(O)₂ NHC(O)CF₃, and (d) S(O)(NH)NH₂ ; R² is selected from the groupconsisting of(a) SR¹¹, (b) OR¹¹, (c) R¹¹, (d) unsubstituted, mono-, di-,tri- or tetra-substituted C₃₋₆ cycloalkenyl wherein the substituents areindependently selected from the group consisting of(1) halo, (2) C₁₋₆alkoxy, (3) C₁₋₆ alkylthio, (4) CN, (5) CF₃, (6) C₁₋₁₀ alkyl, (7) N₃,(8) --CO₂ H, (9) --CO₂ --C₁₋₆ alkyl, (10) --C(R¹²)(R¹³)--OH, (11)--C(R¹²)(R¹³)--O--C₁₋₄ alkyl, (12) --C₁₋₆ alkyl-CO₂ --R¹² ; (13)benzyloxy, (14) --O--(C₁₋₁₀ alkyl)-CO₂ R¹², and (15) --O--(C₁₋₁₀alkyl)-NR¹² R¹³ ; (e) a mono-, di-, tri- or tetra-substitutedheterocycloalkyl group of 5, 6 or 7 members or a benzoheterocyclewherein said heterocycloalkyl or benzoheterocycle contains 1 or 2heteroatoms selected from O, S, or N and optionally contains a carbonylgroup or a sulfonyl group, and wherein said substituents areindependently selected from the group consisting of(1) halo, (2) C₁₋₆alkyl, (3) C₁₋₆ alkoxy, (4) C₁₋₆ alkylthio, (5) CN, (6) CF₃, (7) N₃, (8)--C(R¹²)(R¹³)--OH, and (9) --C(R¹²)(R¹³)--O--C₁₋₆ alkyl; (f)phenylacetylene or mono- or di-substituted phenylacetylene wherein thesubstituents are independently selected from the group consisting of(1)halo, (2) C₁₋₆ alkoxy, (3) C₁₋₆ alkylthio, (4) CN, (5) CF₃, (6) C₁₋₆alkyl, (7) N₃, (8) --CO₂ H, (9) --CO₂ --C₁₋₆ alkyl, (10)--C(R¹²)(R¹³)--OH, (11) --C(R¹²)(R¹³)--O--C₁₋₄ alkyl, (12) --C₁₋₆alkyl-CO₂ --R¹², (13) benzyloxy, (14) --O--(C₁₋₆ alkyl)-CO₂ R¹², (15)--O--(C₁₋₆ alkyl)-NR¹² R¹³, and R³ is hydrogen, C₁₋₁₀ alkyl, CH₂ OR⁸,CN, CH₂ CN, or C₁₋₆ fluoroalkyl, F, CONR⁸ ₂ ; R⁴ is(a) hydrogen, (b)C₁₋₆ alkyl, (c) C₁₋₆ alkoxy, (d) C₁₋₆ alkylthio, (e) --OH, (f) --OCOR⁸,(g) --SH, or R³ and R⁴ together with the carbon to which they areattached form a monocyclic ring of 3, 4, 5, 6, or 7 members which ringoptionally contains one or two heteroatoms selected from O, S or N; R⁵is selected from the group consisting of(a) OR¹⁷, (b) SR¹⁸, and (c)NHS(O)₂ R¹⁸ ; each R⁸ is independently selected from the groupconsisting of(a) hydrogen and (b) R⁹ ; each R⁹ is independently selectedfrom the group consisting of(a) C₁₋₁₀ alkyl, (b) --C₁₋₁₀ alkyl-CO₂ H (c)C₁₋₁₀ alkyl-NH₂ (d) phenyl or mono-, di- or tri-substituted phenylwherein the substituents are independently selected from halo, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alklyCO₂ H, C₁₋₁₀ alkylNH₂,CN, CO₂ H and CF₃, (e) benzyl or mono-, di- or tri-substituted benzylwherein the substituents are independently selected from halo, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylCO₂ H, C₁₋₁₀ alkylNH₂,CN, CO₂ H and CF₃, (f) C₃₋₁₀ cycloalkyl, (g) C₁ -C₁₀ alkanoyl, and (h)benzoyl or mono-, di-, or trisubstituted benzoyl wherein thesubstituents are independently selected from halo, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, C₁₋₁₀ alkylthio, C₁₋₁₀ alkylCO₂ H, --C₁₋₁₀ alkylNH₂, CN, CO₂ Hand CF₃, R¹¹ is selected from the group consisting of(a) C₁₋₁₀ alkyl,(b) C₃₋₁₀ cycloalkyl, (c) unsubstituted, mono-, di- or tri-substitutedphenyl or naphthyl wherein the substituents are independently selectedfrom the group consisting of(1) halo, (2) C₁₋₆ alkoxy, (3) C₁₋₆alkylthio, (4) CN, (5) CF₃, (6) C₁₋₆ alkyl, (7) N₃, (8) --CO₂ H, (9)--CO₂ --C₁₋₆ alkyl, (10) --C(R¹²)(R¹³)--OH, (11) --C(R¹²)(R¹³)--O--C₁₋₄alkyl, (12) --C₁₋₆ alkyl-CO₂ --R¹², (13) benzyloxy, (14) --O--(C₁₋₆alkyl)-CO₂ R¹², and (15) --O--(C₁₋₆ alkyl)-NR¹² R¹³, (d) unsubstituted,mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is amonocyclic aromatic ring of 5 atoms, said ring having one hetero atomwhich is S, O, or N, and optionally 1, 2, or 3 additional N atoms; orsaid heteroaryl is a monocyclic ring of 6 atoms, said ring having onehetero atom which is N, and optionally 1, 2, or 3 additional N atoms,and wherein said substituents are independently selected from the groupconsisting of(1) halo, (2) C₁₋₆ alkyl, (3) C₁₋₆ alkoxy, (4) C₁₋₆alkylthio, (5) CN, (6) CF₃, (7) N₃, (8) --C(R¹²)(R¹³)--OH, and (9)--C(R¹²)(R¹³)--O--C₁₋₆ alkyl; (e) unsubstituted, mono- or di-substitutedbenzoheterocycle in which the benzoheterocycle is a 5, 6, or 7-memberedring which contains 1 or 2 heteroatoms independently selected from O, S,or N and optionally a carbonyl group or a sulfonyl group, wherein saidsubstituents are selected from the group consisting of(1) halo, (2) C₁₋₆alkyl, (3) C₁₋₆ alkoxy, (4) C₁₋₆ alkylthio, (5) CN, (6) CF₃, (7) N₃, (8)--C(R¹²)(R¹³)--OH, and (9) --C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl; (f)unsubstituted, mono- or di-substituted benzocarbocycle in which thecarbocycle is a 5, 6, or 7-membered ring which optionally contains acarbonyl group, wherein said substituents are independently selectedfrom the group consisting of(1) halo, (2) C₁₋₆ alkyl, (3) C₁₋₆ alkoxy,(4) C₁₋₆ alkylthio, (5) CN, (6) CF₃, (7) N₃, (8) --C(R¹²)(R¹³)--OH, and(9) --C(R¹²)(R¹³)--O--C₁₋₁₀ alkyl; each R¹² or R¹³ is independentlyselected from the group consisting of(a) hydrogen, and (b) C₁₋₆ alkyl,each R¹⁷ is independently selected from the group consisting of(a)hydrogen and (b) R¹⁸ ; and each R¹⁸ is independently selected from thegroup consisting of(a) C₁₋₆ alkyl, (b) --C₁₋₁₀ alkyl-CO₂ H (c) C₁₋₆alkanoyl, and (d) H-(oxyethyl)n wherein n is 1 to
 6. 4. A compoundaccording to claim 3 wherein:R¹ is selected from the group consistingof(a) S(O)₂ CH₃, and (b) S(O)₂ NHR⁸ ; R² is selected from the groupconsisting of(a) OR¹¹, (b) R¹¹, (c) a mono-, di-, tri- ortetra-substituted heterocycloalkyl group of 5, 6 or 7 members or abenzoheterocycle wherein said heterocycloalkyl or benzoheterocyclecontains 1 or 2 heteroatoms selected from O, S, or N and optionallycontains a carbonyl group or a sulfonyl group, and wherein saidsubstituents are independently selected from the group consisting of(1)halo, (2) C₁₋₄ alkyl, (3) C₁₋₄ alkoxy, (4) C₁₋₄ alkylthio, (5) CF₃, and(6) --C(R¹²)(R¹³)--OH; (d) phenylacetylene or mono- or di-substitutedphenylacetylene wherein the substituents are independently selected fromthe group consisting of(1) halo, (2) C₁₋₄ alkyl, (3) C₁₋₄ alkoxy, (4)C₁₋₄ alkylthio, (5) CF₃, and (6) --C(R¹²)(R¹³)--OH; R³ is hydrogen, C₁₋₄alkyl, CH₂ OH, or C₁₋₆ fluoroalkyl, F, CONH₂ ; R⁴ is(a) hydrogen, (b)C₁₋₄ alkyl, (c) C₁₋₄ alkoxy, (d) C₁₋₄ alkylthio, (e) --OH, or R³ and R⁴together with the carbon to which they are attached form a monocyclicring of 3, 4, 5, 6, or 7 members which ring optionally contains one ortwo heteroatoms selected from O, S or N; R⁵ is selected from the groupconsisting of(a) OR¹⁷, and (b) SR¹⁸ ; each R⁸ is independently selectedfrom the group consisting of(a) hydrogen and (b) R⁹ ; each R⁹ isindependently selected from the group consisting of(a) C₁₋₄ alkyl, (b)--C₁₋₄ alkyl-CO₂ H (c) phenyl or mono-, di- or tri-substituted phenylwherein the substituents are independently selected from halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alklyCO₂ H, C₁₋₄ alkylNH₂, CN,CO₂ H and CF₃, (f) C₃₋₆ cycloalkyl, (g) C₁ -C₄ alkanoyl, and (h) benzoylor mono-, di-, or trisubstituted benzoyl wherein the substituents areindependently selected from halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylCO₂ H, --C₁₋₄ alkylNH₂, CN, CO₂ H and CF₃, R¹¹ isselected from the group consisting of(a) unsubstituted, mono- ordi-substituted phenyl wherein the substituents are independentlyselected from the group consisting of(1) halo, (2) C₁₋₄ alkoxy, (3) C₁₋₄alkylthio, (5) CF₃, (6) C₁₋₄ alkyl, (7) --CO₂ H, (8) --CO₂ --C₁₋₆ alkyl,(9) --C(R¹²)(R¹³)--OH, (d) unsubstituted, mono- or di-substitutedheteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5atoms, said ring having one hetero atom which is S, O, or N, andoptionally 1, 2, or 3 additional N atoms; or said heteroaryl is amonocyclic ring of 6 atoms, said ring having one hetero atom which is N,and optionally 1, 2, or 3 additional N atoms, and wherein saidsubstituents are independently selected from the group consisting of(1)halo, (2) C₁₋₄ alkoxy, (3) C₁₋₄ alkylthio, (4) CF₃, (5) C₁₋₄ alkyl, (6)--CO₂ H, (7) --CO₂ --C₁₋₆ alkyl, (8) --C(R¹²)(R¹³)--OH, (e)unsubstituted, mono- or di-substituted benzoheterocycle in which thebenzoheterocycle is a 5, 6, or 7-membered ring which contains 1 or 2heteroatoms independently selected from O, S, or N and optionally acarbonyl group or a sulfonyl group, wherein said substituents areselected from the group consisting of(1) halo, (2) C₁₋₄ alkoxy, (3) C₁₋₄alkylthio, (4) CF₃, (5) C₁₋₄ alkyl, (6) --CO₂ H, (7) --CO₂ --C₁₋₆ alkyl,(8) --C(R¹²)(R¹³)--OH, (f) unsubstituted, mono- or di-substitutedbenzocarbocycle in which the carbocycle is a 5, 6, or 7-membered ringwhich optionally contains a carbonyl group, wherein said substituentsare independently selected from the group consisting of(1) halo, (2)C₁₋₄ alkoxy, (3) C₁₋₄ alkylthio, (4) CF₃, (5) C₁₋₄ alkyl, (6) --CO₂ H,(7) --CO₂ --C₁₋₆ alkyl, (8) --C(R¹²)(R¹³)--OH, each R¹² or R¹³ isindependently selected from the group consisting of(a) hydrogen, and (b)C₁₋₆ alkyl, each R¹⁷ is independently selected from the group consistingof(a) hydrogen and (b) R¹⁸ ; and each R¹⁸ is independently selected fromthe group consisting of(a) C₁₋₄ alkyl, (b) --C₁₋₄ alkyl-CO₂ H (c) C₁₋₆alkanoyl, and (d) H-(oxyethyl)n wherein n is 1 to
 4. 5. A compoundaccording to claim 4 wherein:R¹ is selected from the group consistingof(a) S(O)₂ CH₃, and (b) S(O)₂ NH₂ ; R² is selected from the groupconsisting of(a) OR¹¹, (b) R¹¹, (c) a mono- or di-substitutedheterocycloalkyl group of 5 or 6 members or a benzoheterocycle whereinsaid heterocycloalkyl or benzoheterocycle contains 1 or 2 heteroatomsselected from O, S, or N and optionally contains a carbonyl group or asulfonyl group, and wherein said substituents are independently selectedfrom the group consisting of(1) halo, (2) C₁₋₃ alkyl, (3) C₁₋₃ alkoxy,(4) C₁₋₃ alkylthio, and (5) CF₃, (d) phenylacetylene or mono- ordi-substituted phenylacetylene wherein the substituents areindependently selected from the group consisting of(1) halo, (2) C₁₋₃alkyl, (3) C₁₋₃ alkoxy, (4) C₁₋₃ alkylthio, and (5) CF₃, R³ is hydrogen,C₁₋₄ alkyl, C₁₋₆ fluoroalkyl or F; R⁴ is(a) hydrogen, (b) C₁₋₃ alkyl,(c) C₁₋₃ alkoxy, (d) C₁₋₃ alkylthio, (e) --OH, or R³ and R⁴ togetherwith the carbon to which they are attached form a monocyclic ring of 3,4, 5 or 6 members which ring optionally contains one or two heteroatomsselected from O, S or N; R⁵ is selected from the group consisting of(a)OR¹⁷, and (b) SR¹⁸ ; each R⁸ is independently selected from the groupconsisting of(a) hydrogen and (b) R⁹ ; each R⁹ is independently selectedfrom the group consisting of(a) C₁₋₄ alkyl, (b) --C₁₋₄ alkyl-CO₂ H (f)C₃₋₆ cycloalkyl, (g) C₁₋₃ alkanoyl, and R¹¹ is selected from the groupconsisting of(a) unsubstituted, mono- or di-substituted phenyl whereinthe substituents are independently selected from the group consistingof(1) F or Cl, (2) C₁₋₄ alkoxy, (3) C₁₋₄ alkylthio, (5) CF₃, (6) C₁₋₄alkyl, and (7) --CO₂ H, (d) unsubstituted, mono- or di-substitutedheteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5atoms, said ring having one hetero atom which is S, O, or N, andoptionally 1, 2, or 3 additional N atoms; or said heteroaryl is amonocyclic ring of 6 atoms, said ring having one hetero atom which is N,and optionally 1, 2, or 3 additional N atoms, and wherein saidsubstituents are independently selected from the group consisting of(1)F or Cl, (2) C₁₋₄ alkoxy, (3) C₁₋₄ alkylthio, (5) CF₃, (6) C₁₋₄ alkyl,and (7) --CO₂ H, (e) unsubstituted, mono- or di-substitutedbenzoheterocycle in which the benzoheterocycle is a 5 or 6-membered ringwhich contains 1 or 2 heteroatoms independently selected from O, S, or Nand optionally a carbonyl group or a sulfonyl group, wherein saidsubstituents are selected from the group consisting of(1) F or Cl, (2)C₁₋₄ alkoxy, (3) C₁₋₄ alkylthio, (5) CF₃, (6) C₁₋₄ alkyl, and (7) --CO₂H, (f) unsubstituted, mono- or di-substituted benzocarbocycle in whichthe carbocycle is a 5 or 6-membered ring which optionally contains acarbonyl group, wherein said substituents are independently selectedfrom the group consisting of(1) F or Cl, (2) C₁₋₄ alkoxy, (3) C₁₋₄alkylthio, (5) CF₃, (6) C₁₋₄ alkyl, and (7) --CO₂ H, each R¹⁷ isindependently selected from the group consisting of(a) hydrogen and (b)R¹⁸ ; and each R¹⁸ is independently selected from the group consistingof(a) C₁₋₄ alkyl, (b) --C₁₋₄ alkyl-CO₂ H (c) C₁₋₄ alkanoyl, and (d)H-(oxyethyl)n wherein n is 1, 2, 3 or
 4. 6. A compound according toclaim 5 wherein:R¹ is selected from the group consisting of(a) S(O)₂CH₃, and (b) S(O)₂ NH₂ ; R² is selected from the group consisting of(a)OR¹¹, (b) R¹¹, (c) a mono- or di-substituted heterocycloalkyl group of 5or 6 members wherein said heterocycloalkyl contains 1 or 2 heteroatomswhich is N and optionally contains a carbonyl group, and wherein saidsubstituents are independently selected from the group consisting of(1)Cl or F, (2) C₁₋₂ alkyl, and (3) C₁₋₂ alkoxy, (d) phenylacetylene ormono- or di-substituted phenylacetylene wherein the substituents areindependently selected from the group consisting of(1) Cl or F, (2) C₁₋₂alkyl, and (3) C₁₋₂ alkoxy, R³ is hydrogen, C₁₋₃ alkyl; R⁴ is hydrogen,C₁₋₃ alkyl; or R³ and R⁴ together with the carbon to which they areattached form a monocyclic ring of 3, 4, 5 or 6 carbon atoms; R⁵ isselected from the group consisting of(a) OR¹⁷, and (b) SR¹⁸ ; each R⁸ isindependently selected from the group consisting of(a) hydrogen and (b)R⁹ ; each R⁹ is independently selected from the group consisting of(a)C₁₋₄ alkyl, (b) --C₁₋₄ alkyl-CO₂ H (f) C₃₋₆ cycloalkyl, and (g) C₁₋₃alkanoyl, R¹¹ is selected from the group consisting of(a) unsubstituted,mono- or di-substituted phenyl wherein the substituents areindependently selected from the group consisting of(1) F or Cl, (2) C₁₋₄alkoxy, (3) C₁₋₄ alkylthio, (5) CF₃, (6) C₁₋₄ alkyl, and (7) --CO₂ H,(d) unsubstituted, mono- or di-substituted heteroaryl wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone hetero atom which is S, O, or N, and optionally 1, 2, or 3additional N atoms; or said heteroaryl is a monocyclic ring of 6 atoms,said ring having one hetero atom which is N, and optionally 1, 2, or 3additional N atoms, and wherein said substituents are independentlyselected from the group consisting of(1) F or Cl, (2) C₁₋₄ alkoxy, (3)C₁₋₄ alkylthio, (5) CF₃, (6) C₁₋₄ alkyl, and (7) --CO₂ H, (e)unsubstituted, mono- or di-substituted benzoheterocycle in which thebenzoheterocycle is a 5 or 6-membered ring which contains 1 or 2heteroatoms independently selected from O, S, or N and optionally acarbonyl group or a sulfonyl group, wherein said substituents areselected from the group consisting of(1) F or Cl, (2) C₁₋₄ alkoxy, (3)C₁₋₄ alkylthio, (5) CF₃, (6) C₁₋₄ alkyl, and (7) --CO₂ H, (f)unsubstituted, mono- or di-substituted benzocarbocycle in which thecarbocycle is a 5 or 6-membered ring which optionally contains acarbonyl group, wherein said substituents are independently selectedfrom the group consisting of(1) F or Cl, (2) C₁₋₄ alkoxy, (3) C₁₋₄alkylthio, (5) CF₃, (6) C₁₋₄ alkyl, and (7) --CO₂ H, each R¹⁷ isindependently selected from the group consisting of(a) hydrogen and (b)R¹⁸ ; and each R¹⁸ is independently selected from the group consistingof(a) C₁₋₄ alkyl, (b) --C₁₋₄ alkyl-CO₂ H (c) C₁₋₆ alkanoyl, and (d)H-(oxyethyl)n wherein n is 1 to
 4. 7. A compound according to claim 6wherein:R¹ is selected from the group consisting of(a) S(O)₂ CH₃, and(b) S(O)₂ NH₂ ; R² is selected from the group consisting of(a) OR¹¹, (b)R¹¹, (c) a mono- or di-substituted heterocycloalkyl group of 5 or 6members wherein said heterocycloalkyl contains 1 or 2 heteroatoms whichis N and optionally contains a carbonyl group, and wherein saidsubstituents are independently selected from the group consisting of(1)Cl or F, (2) C₁₋₂ alkyl, and (3) C₁₋₂ alkoxy; R³ is hydrogen, methyl orethyl; R⁴ is hydrogen, methyl or ethyl; R⁵ is OR¹⁷ ; R¹¹ is selectedfrom the group consisting of(a) unsubstituted, mono- or di-substitutedphenyl wherein the substituents are independently selected from thegroup consisting of(1) F or Cl, (2) C₁₋₄ alkoxy, (3) C₁₋₄ alkylthio, (5)CF₃, (6) C₁₋₄ alkyl, and (7) --CO₂ H, (b) unsubstituted, mono- ordi-substituted heteroaryl wherein the heteroaryl is a monocyclicaromatic ring of 5 atoms, said ring having one hetero atom which is S,O, or N, and optionally 1, 2, or 3 additional N atoms; or saidheteroaryl is a monocyclic ring of 6 atoms, said ring having one heteroatom which is N, and optionally 1, 2, or 3 additional N atoms, andwherein said substituents are independently selected from the groupconsisting of(1) F or Cl, (2) C₁₋₄ alkoxy, (3) C₁₋₄ alkylthio, (5) CF₃,(6) C₁₋₄ alkyl, and (7) --CO₂ H, each R¹⁷ is independently selected fromthe group consisting of(a) hydrogen and (b) R¹⁸ ; and each R¹⁸ isindependently selected from the group consisting of(a) C₁₋₄ alkyl, (b)--C₁₋₄ alkyl-CO₂ H (c) C₁₋₆ alkanoyl, and (d) H-(oxyethyl)n wherein n is2, 3 or
 4. 8. A compound according to claim 7 wherein:R¹ is selectedfrom the group consisting of(a) S(O)₂ CH₃, and (b) S(O)₂ NH₂ ; R² isselected from the group consisting of(a) OR¹¹, (b) R¹¹, (c) a mono- ordi-substituted heterocycloalkyl group of 5 or 6 members wherein saidheterocycloalkyl contains 1 or 2 heteroatoms which is N and optionallycontains a carbonyl group, and wherein said substituents areindependently selected from the group consisting of(1) Cl or F, (2) C₁₋₂alkyl, and (3) C₁₋₂ alkoxy; R³ is hydrogen, methyl or ethyl; R⁴ ishydrogen, methyl or ethyl; R⁵ is OR¹⁷ ; R¹¹ is selected from the groupconsisting of(a) unsubstituted, mono- or di-substituted phenyl whereinthe substituents are independently selected from the group consistingof(1) F or Cl, (2) C₁₋₄ alkoxy, (3) C₁₋₄ alkylthio, (5) CF₃, (6) C₁₋₄alkyl, and (7) --CO₂ H, (b) unsubstituted, mono- or di-substitutedheteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5atoms, said ring having one hetero atom which is S, O, or N, andoptionally 1, 2, or 3 additional N atoms; or said heteroaryl is amonocyclic ring of 6 atoms, said ring having one hetero atom which is N,and optionally 1, 2, or 3 additional N atoms, and wherein saidsubstituents are independently selected from the group consisting of(1)F or Cl, (2) C₁₋₄ alkoxy, (3) C₁₋₄ alkylthio, (5) CF₃, (6) C₁₋₄ alkyl,and (7) --CO₂ H, each R¹⁷ is independently selected from the groupconsisting of(a) hydrogen and (b) R¹⁸ ; and each R¹⁸ is independentlyselected from the group consisting of(a) C₁₋₄ alkyl, (b) --C₁₋₄alkyl-CO₂ H (c) C₁₋₆ alkanoyl, and (d) H-(oxyethyl)n wherein n is 2, 3or
 4. 9. A compound according to claim 8 wherein:R¹ is selected from thegroup consisting of(a) S(O)₂ CH₃, and (b) S(O)₂ NH₂ ; R² is selectedfrom the group consisting of(a) OR¹¹, (b) R¹¹, R³ is hydrogen, methyl orethyl; R⁴ is hydrogen, methyl or ethyl; R⁵ is OR¹⁷ ; R¹¹ is anunsubstituted, mono- or di-substituted phenyl wherein the substituentsare independently selected from the group consisting of(1) F or Cl, (2)C₁₋₄ alkoxy, (3) C₁₋₄ alkylthio, (5) CF₃, (6) C₁₋₄ alkyl, and (7) --CO₂H, each R¹⁷ is independently selected from the group consisting of(a)hydrogen and (b) R¹⁸ ; and each R¹⁸ is independently selected from thegroup consisting of(a) C₁₋₃ alkyl, (b) --C₁₋₃ alkyl-CO₂ H (c) C₁₋₃alkanoyl, and (d) H-(oxyethyl)n wherein n is 2 to
 4. 10. A compoundaccording to claim 8 whereinR² is a mono- or di-substituted heteroarylwherein heteroaryl is selected from the group consisting of(1) furanyl,(2) diazinyl, (3) imidazolyl, (4) isooxazolyl, (5) isothiazolyl, (6)oxadiazolyl, (7) oxazolyl, (8) pyrazolyl, (9) pyridyl, (10) pyrrolyl,(11) tetrazinyl, (12) tetrazolyl, (13) thiadiazolyl, (14) thiazolyl,(15) thienyl, (16) triazinyl, or (17) triazolyl, and the substituentsare selected from the group consisting of(1) hydrogen, (2) halo, (3)C₁₋₄ alkyl, (4) C₁₋₄ alkoxy, (5) C₁₋₄ alkylthio, (6) CN, and (7) CF₃.11. A compound according to claim 10 whereinR² is a mono- ordi-substituted heteroaryl wherein heteroaryl is selected from the groupconsisting of(1) furanyl, (2) diazinyl, (3) imidazolyl, (4) isooxazolyl,(5) isothiazolyl, (6) oxadiazolyl, (7) oxazolyl, (8) pyrazolyl, (9)pyridyl, (10) pyrrolyl, (11) thiazolyl, (12) thienyl, wherein thesubstituents are selected from the group consisting of(1) hydrogen, (2)halo, (3) C₁₋₃ alkyl, (4) C₁₋₃ alkoxy, (7) CF₃.
 12. A compound accordingto claim 11 whereinR² is a mono- or di-substituted heteroaryl whereinheteroaryl is selected from the group consisting of(1) furanyl, (2)diazinyl, (3) imidazolyl, (4) oxadiazolyl, (5) pyrazolyl, (6) pyridyl,(7) pyrrolyl, (8) thiazolyl, (9) thienyl, wherein the substituents areselected from the group consisting of(1) hydrogen, (2) halo, (3) methyl,(4) methoxy, and (5) CF₃.
 13. A compound according to claim 12 whereinR²is a mono- or di-substituted heteroaryl wherein heteroaryl is selectedfrom the group consisting of(1) furanyl, (2) diazinyl, (3) imidazolyl,(4) oxadiazolyl, (5) pyrazolyl, (6) pyridyl, (7) thiazolyl, (8) thienyl,wherein the substituents are selected from the group consisting of(1)hydrogen, (2) Cl or F, (3) methyl, (4) methoxy, (5) CF3.
 14. A compoundaccording to claim 1 selected from the group consisting of(a)5,5-Dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,(b)3-(3,5-Difluorophenyl)-5,5-dimethyl-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,(c)5,5-Dimethyl-3-(4-fluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,(d)5,5-Dimethyl-3-(4-fluorophenyl)-2-methoxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,(e)5,5-Dimethyl-2-ethoxy-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,(f)5,5-Dimethyl-3-(3-fluorophenyl)-2-isopropoxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,(g)5,5-Dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-methylthio-2,5-dihydrofuran,(h)5-Ethyl-3-(4-fluorophenyl)-2-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,(i)5,5-Dimethyl-3-(3-fluorophenoxy)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,(j)5,5-Dimethyl-3-(3,4-difluorophenoxy)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,(k)3-(3,4-Difluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran(l)2-Acetoxy-5,5-dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran,(m)Sodium(5,5-dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran-2-yloxy)actetate, (n)3-isopropoxy-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol),(o) 5,5-Dimethyl-4-(4-methylsulfonylphenyl)-3phenyl-2,5-dihydrofuran-2-ol), (p)3-(3-Fluorophenyl)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol),(q)3-(3,4-Difluorophenyl)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol),(r)3-(1-Cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol),(s)3-(Cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran-2-ol),and (t)3-(3,4-Difluorophenoxy)-5-methyl-4-(4-methylsulfonylphenyl)-5-2,2,2-trifluoroethyl)-2,5-dihydrofuran-2-ol).15. A pharmaceutical composition for treating an inflammatory diseasesusceptable to treatment with an non-steroidal anti-inflammatory agentcomprising:a non-toxic therapeutically effective amount of a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 16. Apharmaceutical composition for treating cyclooxygenase mediated diseasesadvantageously treated by an active agent that selectively inhibitsCOX-2 in preference to COX-1 comprising:a non-toxic therapeuticallyeffective amount of a compound according to claim 1 and apharmaceutically acceptable carrier.
 17. A method of treating aninflammatory disease susceptable to treatment with an non-steroidalanti-inflammatory agent comprising:administration to a patient in needof such treatment of a non-toxic therapeutically effective amount of acompound according to claim 1 and a pharmaceutically acceptable carrier.18. A method of treating cyclooxygenase mediated diseases advantageouslytreated by an active agent that selectively inhibits COX-2 in preferenceto COX-1 comprising:administration to a patient in need of suchtreatment of a non-toxic therapeutically effective amount of a compoundaccording to claim 1.